{{Short description|Genetic abnormality in leukemia cancer cells}} {{Infobox medical condition | name = Philadelphia chromosome | synonyms = | image = Bcrablmet.jpg | caption = A metaphase cell positive for the bcr/abl rearrangement using FISH | pronounce = | field = | symptoms = | complications = | onset = | duration = | types = | causes = | risks = | diagnosis = | differential = | prevention = | treatment = | medication = | prognosis = | frequency = | deaths = }} The '''Philadelphia chromosome''' or '''Philadelphia translocation''' ('''Ph''') is an abnormal version of chromosome 22 where a part of the ''Abelson murine leukemia'' 1 (''ABL1'') gene on chromosome 9 breaks off and attaches to the ''breakpoint cluster region'' (''BCR'') gene in chromosome 22.<ref name=":0">{{Cite journal |last1=Sampaio |first1=Mariana Miranda |last2=Santos |first2=Maria Luísa Cordeiro |last3=Marques |first3=Hanna Santos |last4=Gonçalves |first4=Vinícius Lima de Souza |last5=Araújo |first5=Glauber Rocha Lima |last6=Lopes |first6=Luana Weber |last7=Apolonio |first7=Jonathan Santos |last8=Silva |first8=Camilo Santana |last9=Santos |first9=Luana Kauany de Sá |last10=Cuzzuol |first10=Beatriz Rocha |last11=Guimarães |first11=Quézia Estéfani Silva |last12=Santos |first12=Mariana Novaes |last13=de Brito |first13=Breno Bittencourt |last14=da Silva |first14=Filipe Antônio França |last15=Oliveira |first15=Márcio Vasconcelos |date=2021-02-24 |title=Chronic myeloid leukemia-from the Philadelphia chromosome to specific target drugs: A literature review |journal=World Journal of Clinical Oncology |volume=12 |issue=2 |pages=69–94 |doi=10.5306/wjco.v12.i2.69 |doi-access=free |issn=2218-4333 |pmc=7918527 |pmid=33680875}}</ref><ref name=":1">{{Cite web |date=2011-02-02 |title=Philadelphia Chromosome |url=https://www.cancer.gov/publications/dictionaries/cancer-terms/def/philadelphia-chromosome |access-date=2025-03-26 |website=www.cancer.gov |language=en}}</ref> The balanced reciprocal translocation between the long arms of 9 and 22 chromosomes [t (9; 22) (q34; q11)] results in the fusion gene ''BCR::ABL1''.<ref name=":1" /> The oncogenic protein with persistently enhanced tyrosine kinase (TK) activity transcribed by the ''BCR''::''ABL1'' fusion gene can lead to rapid, uncontrolled growth of immature white blood cells that accumulates in the blood and bone marrow.<ref name=":2">{{Cite journal |last1=Kang |first1=Zhi-Jie |last2=Liu |first2=Yu-Fei |last3=Xu |first3=Ling-Zhi |last4=Long |first4=Zi-Jie |last5=Huang |first5=Dan |last6=Yang |first6=Ya |last7=Liu |first7=Bing |last8=Feng |first8=Jiu-Xing |last9=Pan |first9=Yu-Jia |last10=Yan |first10=Jin-Song |last11=Liu |first11=Quentin |date=December 2016 |title=The Philadelphia chromosome in leukemogenesis |journal=Chinese Journal of Cancer |language=en |volume=35 |issue=1 |page=48 |doi=10.1186/s40880-016-0108-0 |doi-access=free |issn=1944-446X |pmc=4896164 |pmid=27233483}}</ref><ref name=":0" />
The Philadelphia chromosome is present in the bone marrow cells of a vast majority ''chronic myelogenous leukemia'' (CML) patients. The expression patterns of different BCR-ABL1 transcripts vary during the progression of CML. Each variant is present in a distinct leukemia phenotype and can be used to predict response to therapy and clinical outcomes. The Ph is also observed in patients with acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), and mixed-phenotype acute leukemia.<ref name=":0" /><ref name=":2" />
==Molecular biology== [[File:PH formation.png|thumb|490x490px|Schematic of the Philadelphia chromosome formation, showcasing exons in the ABL1 and BCR gene, and the central breakpoint regions<ref>{{Cite journal |last1=Abdulmawjood |first1=Bilal |last2=Costa |first2=Beatriz |last3=Roma-Rodrigues |first3=Catarina |last4=Baptista |first4=Pedro V. |last5=Fernandes |first5=Alexandra R. |date=2021-11-19 |title=Genetic Biomarkers in Chronic Myeloid Leukemia: What Have We Learned So Far? |journal=International Journal of Molecular Sciences |language=en |volume=22 |issue=22 |article-number=12516 |doi=10.3390/ijms222212516 |doi-access=free |issn=1422-0067 |pmc=8626020 |pmid=34830398}}</ref>]] The chromosomal abnormality in the Philadelphia chromosome from the reciprocal translocation t(9;22)(q34;q11), is the result of fragments from chromosomes 9 and 22 swapping places.<ref name=":2" /> The ''ABL'' proto-oncogene 1 on chromosome 9, from region q34, is juxtaposed with a portion of the ''BCR'' gene on chromosome 22, region q11.2.<ref name=":9" /> The derivative chromosome 22 produced by this translocation is known as the Philadelphia chromosome. This translocation creates a fusion gene, ''BCR::ABL1'', which codes for a constitutively active ("always on") tyrosine kinase signaling protein, driving uncontrolled cell division.<ref name=":5" /><ref name=":2" />
The formation of the Philadelphia chromosome is due to the fusion of the BCR and ABL1 genes. ''ABL1'' is derived from ''Abelson murine leukemia,'' a retrovirus that causes leukemia and lymphoma in mice. It is named after Herbert T. Abelson, who discovered it in 1970.<ref>{{Cite journal |last1=Abelson |first1=H. T. |last2=Rabstein |first2=L. S. |date=August 1970 |title=Lymphosarcoma: virus-induced thymic-independent disease in mice |journal=Cancer Research |volume=30 |issue=8 |pages=2213–2222 |issn=0008-5472 |pmid=4318922}}</ref><ref>{{Cite journal |last1=Jabbour |first1=Elias |last2=Kantarjian |first2=Hagop |date=November 2024 |title=Chronic myeloid leukemia: 2025 update on diagnosis, therapy, and monitoring |url=https://onlinelibrary.wiley.com/doi/10.1002/ajh.27443 |journal=American Journal of Hematology |language=en |volume=99 |issue=11 |pages=2191–2212 |doi=10.1002/ajh.27443 |pmid=39093014 |issn=0361-8609|url-access=subscription }}</ref><ref name=":10">{{Cite journal |last1=Soverini |first1=Simona |last2=Mancini |first2=Manuela |last3=Bavaro |first3=Luana |last4=Cavo |first4=Michele |last5=Martinelli |first5=Giovanni |date=2018-02-19 |title=Chronic myeloid leukemia: the paradigm of targeting oncogenic tyrosine kinase signaling and counteracting resistance for successful cancer therapy |journal=Molecular Cancer |volume=17 |issue=1 |page=49 |doi=10.1186/s12943-018-0780-6 |issn=1476-4598 |pmc=5817796 |pmid=29455643 |doi-access=free}}</ref> BCR stands for ''breakpoint cluster region'' because of the relatively small genomic region where the DNA breaks occurs.<ref name=":10" /> The fusion can happen at different points in the BCR gene, where the gene will fuse with exon 2 of ABL (breakpoints in exon 3 of ''ABL1'' have also been observed, but are less frequent). The ''BCR::ABL1'' oncogene exists in three primary isoforms depending on the breakpoint site of the BCR gene and are named after the fuse region, and the molecular weight of the transcribed ''BCR-ABL1'' fusion protein, and all encode for a tyrosine kinase protein. The e1a2 transcript is a fusion between exon 1 of BCR, also called the minor breakpoint region (m-BCR), and exon 2 of ABL1 and encodes an oncoprotein of 185-190 kDa, referred to as P190.<ref name=":11">{{Cite journal |last1=Soverini |first1=Simona |last2=Albano |first2=Francesco |last3=Bassan |first3=Renato |last4=Fabbiano |first4=Francesco |last5=Ferrara |first5=Felicetto |last6=Foà |first6=Robin |last7=Olivieri |first7=Attilio |last8=Rambaldi |first8=Alessandro |last9=Rossi |first9=Giuseppe |last10=Sica |first10=Simona |last11=Specchia |first11=Giorgina |last12=Venditti |first12=Adriano |last13=Barosi |first13=Giovanni |last14=Pane |first14=Fabrizio |date=2020 |title=Next-generation sequencing for BCR-ABL1 kinase domain mutations in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A position paper |journal=Cancer Medicine |language=en |volume=9 |issue=9 |pages=2960–2970 |doi=10.1002/cam4.2946 |issn=2045-7634 |pmc=7196068 |pmid=32154668}}</ref><ref>{{Cite journal |last1=Jacobs |first1=Koen |last2=Moerman |first2=Alena |last3=Vandepoele |first3=Karl |last4=Abeele |first4=Tim Van den |last5=De Mulder |first5=Katrien |last6=Steel |first6=Eva |last7=Clauwaert |first7=Maxim |last8=Louagie |first8=Henk |date=October 2024 |title=Variant-specific BCR::ABL1 quantification discrepancy in chronic myeloid leukemia |url=https://onlinelibrary.wiley.com/doi/10.1111/ijlh.14320 |journal=International Journal of Laboratory Hematology |language=en |volume=46 |issue=5 |pages=910–917 |doi=10.1111/ijlh.14320 |pmid=38840510 |issn=1751-5521|url-access=subscription }}</ref> ''BCR::ABL1'' is associated with around 20-30% of all Philadelphia chromosome positive B-cell ALL (ph+ B-ALL) and is the most genetic subgroup of B-ALL. The incident rate for ALL is age related, as the incident rate increases to 50% for ALL in patients aged 50 years and older. where P190 is associated with 60-80% of these.<ref name=":9" /><ref name=":5" /><ref>{{Cite journal |last1=Catalano |first1=Gianfranco |last2=Niscola |first2=Pasquale |last3=Banella |first3=Cristina |last4=Diverio |first4=Daniela |last5=Trawinska |first5=Malgorzata Monika |last6=Fratoni |first6=Stefano |last7=Iazzoni |first7=Rita |last8=De Fabritiis |first8=Paolo |last9=Abruzzese |first9=Elisabetta |last10=Noguera |first10=Nelida Ines |date=2020-10-27 |title=NPM1 Mutated, BCR-ABL1 Positive Myeloid Neoplasms: Review of Literature |url=https://www.mjhid.org/index.php/mjhid/article/view/4384 |journal=Mediterranean Journal of Hematology and Infectious Diseases |volume=12 |issue=1 |pages=e2020083 |doi=10.4084/mjhid.2020.083 |issn=2035-3006 |pmc=7643801 |pmid=33194157}}</ref> The e13a2 and e14a2 transcripts found in the major breakpoint region (M-BCR), which consists of exons 12 through 16. These transcripts encode for a oncoprotein of size 210kDa, and is referred to as P210. P210 is associated with over 95% of CML cases, with a 50/50 split between the e13a2 and e14a2 variants. Additionally, e13a2 and e14a2 has been found to be co-expressed in an estimated 5-10% of CML patients. P210 is also found to be present in 40% of adult and 10% of child B-ALL cases.<ref name=":12">{{Cite journal |last1=Molica |first1=Matteo |last2=Abruzzese |first2=Elisabetta |last3=Breccia |first3=Massimo |date=2020-08-29 |title=Prognostic Significance of Transcript-Type BCR-ABL1 in Chronic Myeloid Leukemia |url=http://www.mjhid.org/index.php/mjhid/article/view/2020.062 |journal=Mediterranean Journal of Hematology and Infectious Diseases |volume=12 |issue=1 |pages=e2020062 |doi=10.4084/mjhid.2020.062 |issn=2035-3006 |pmc=7485470 |pmid=32952973}}</ref> CML has an incidence of 50 cases per million per year<ref name=":13">{{Citation |last1=Haider |first1=Mobeen Z. |title=Genetics, Philadelphia Chromosome |date=2025 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK560689/ |access-date=2025-03-31 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=32809524 |last2=Anwer |first2=Faiz}}</ref> Lastly, the e19a2 transcript, located in the μ-BCR region, produces an oncoprotein of 230kDa which is referred to as P230. This variant is uncommon in comparison, and has been linked to the rare disease chronic neutrophilic leukemia (CNL), which falls under mixed-phenotype acute leukemias.<ref name=":13" />
Detection of these variants is carried out using methods such as Sanger sequencing, reverse transcription polymerase chain reaction (RT-PCR), qPCR, Flourescense In Situ Hybridization (FISH), and southern blotting.<ref name=":12" /> However, many laboratories are working on incorporating Next Generation Sequencing (NGS) into routine diagnostic analysis as NGS technology is rapidly improving, and will in the near future enable full clinical sequencing of the entire gene.<ref name=":11" />
The normal ''BCR'' gene is ubiquitously expressed cytoplasmic protein with many known functionalities. ''ABL1'' gene expresses a membrane-associated protein, a nonreceptor protein-tyrosine kinase. ''ABL1'' is linked to multiple processes related to cell growth and survival, such as cytoskeleton and actin remodelling, and inhibition of cell cycle progression. ABL1 can also be found translocated in the nucleus and has DNA binding capabilities, as it is involved in DNA damage control and repair, and apoptosis. The ''BCR-ABL1'' transcript is also translated into a tyrosine kinase containing domains from both the ''BCR'' and ''ABL1'' genes. The activity of tyrosine kinases is typically regulated in an auto-inhibitory fashion, but the ''BCR-ABL1'' fusion gene codes for a protein that is constitutively activated, leading to impaired DNA binding and unregulated cell division (i.e. cancer).<ref>{{Cite journal |last1=Osman |first1=Afaf E.G. |last2=Deininger |first2=Michael W. |date=September 2021 |title=Chronic Myeloid Leukemia: Modern therapies, current challenges and future directions |journal=Blood Reviews |language=en |volume=49 |article-number=100825 |doi=10.1016/j.blre.2021.100825 |pmc=8563059 |pmid=33773846}}</ref><ref>{{Cite journal |last=Roskoski |first=Robert |date=April 2022 |title=Targeting BCR-Abl in the treatment of Philadelphia-chromosome positive chronic myelogenous leukemia |url=https://linkinghub.elsevier.com/retrieve/pii/S1043661822001013 |journal=Pharmacological Research |language=en |volume=178 |article-number=106156 |doi=10.1016/j.phrs.2022.106156|pmid=35257901 |url-access=subscription }}</ref>
== Mechanisms == The formation of the ''BCR::ABL1'' oncogene leads to a constitutively active Tyrosine kinase, which is important for transformation of hematopoietic cells. Kinases are enzymes that add phosphate groups to their substrates. In cell biology and cell signalling, phosphorylated substrates are mainly used as a "on" signal, usually setting in motion a cascade of downstream signalling pathways. The high activity of TK leads to a chronic activation of signalling pathways associated with all stages of cell transformation. Resulting in uncontrolled cell proliferation, blocked cell differentiation, and inhibited apoptosis. Meaning cells with the ''BCR::ABL1'' fusion multiply uncontrollably, without differentiating into mature white blood cells that live longer due to a lack of apoptosis promoting signals. This leads to a buildup of these immature white blood cells in the bloodstream<ref name=":13" /><ref>{{Cite journal |last1=Sattler |first1=Martin |last2=Griffin |first2=James D. |date=April 2003 |title=Molecular mechanisms of transformation by the BCR-ABL oncogene |url=https://linkinghub.elsevier.com/retrieve/pii/S0037196303807746 |journal=Seminars in Hematology |language=en |volume=40 |issue=2 Suppl 2 |pages=4–10 |doi=10.1053/shem.2003.50034|pmid=12783368 |url-access=subscription }}</ref> There are several signalling pathways associated with the ''BCR::ABL1'' pathogenesis, such as: the Mitogen-activated protein kinase (MAPK/RAS) pathway, PI3K-AKT-mTOR (PAM) pathway, Janus kinase (JAK) - Signal transducers and activators of transcription (STAT) pathway and the Protein Phosphatase 2A (PP2A) tumour suppressor gene –β-catenin pathway.
===MAPK Pathway=== The MAPK pathway includes several key signalling components, and phosphorylation events known to play a crucial part in carcinogenesis. MAPK is composed of multiple signalling cascades, of which the RAS-RAF-MEK-ERK signalling pathway can be found. This pathway is known to play a vital role in cell development, proliferation and survival. Mutations in, and abnormal activation of this pathway will induce tumours, being present in 30% of all cancers. ''BCR::ABL1'' fusions will create constitutively active tyrosine kinases. BCR::ABL1 contains a kinase domain containing Tyr 177, which is a binding site for growth factor receptor binding protein 2 (GRB2). GRB2 binds to a protein called son of sevenless (SOS), a guanine nucleotide exchange factor (GEF). SOS facilitates the conversion of inactive RAS-GDP to active RAS-GTP, which turns on the cascade of enzymes which the RAS-RAF-MEK-ERK pathway is composed of. All steps in this pathway are phosphorylation of enzyme downstream of the signalling pathway, which ends with ERK which in turn phosphorylates hundreds of substrates in the cytoplasm and nucleus which regulate many cellular processes including proliferation, survival, and growth.<ref>{{Cite journal |last=Al Hamad |first=Mohammad |date=2022-02-09 |title=Contribution of BCR-ABL molecular variants and leukemic stem cells in response and resistance to tyrosine kinase inhibitors: a review |journal=F1000Research |language=en |volume=10 |page=1288 |doi=10.12688/f1000research.74570.2 |doi-access=free |issn=2046-1402 |pmc=8886173 |pmid=35284066}}</ref><ref>{{Cite journal |last1=Vendramini |first1=Elena |last2=Bomben |first2=Riccardo |last3=Pozzo |first3=Federico |last4=Bittolo |first4=Tamara |last5=Tissino |first5=Erika |last6=Gattei |first6=Valter |last7=Zucchetto |first7=Antonella |date=2022-01-28 |title=KRAS and RAS-MAPK Pathway Deregulation in Mature B Cell Lymphoproliferative Disorders |journal=Cancers |language=en |volume=14 |issue=3 |page=666 |doi=10.3390/cancers14030666 |doi-access=free |issn=2072-6694 |pmc=8833570 |pmid=35158933}}</ref><ref name=":14" /> The RAS/RAF/MEK/ERK pathway is also implicated in overexpression of osteopontin (OPN), which is important for maintenance of the hematopoietic stem cell niche, which indirectly influences unchecked proliferation characteristic of leukemic cells. The RAS-MAPK pathway is associated with many types of cancers, including CML and ph+ ALL, being also linked to imatinib resistance in some cases.<ref name=":13" />
thumb|767x767px|Overview map of enzymes which compose and are impacted by the RAS pathway<ref name=":14">{{Cite journal |last1=Santarpia |first1=Libero |last2=Lippman |first2=Scott M |last3=El-Naggar |first3=Adel K |date=January 2012 |title=Targeting the MAPK–RAS–RAF signaling pathway in cancer therapy |journal=Expert Opinion on Therapeutic Targets |language=en |volume=16 |issue=1 |pages=103–119 |doi=10.1517/14728222.2011.645805 |issn=1472-8222 |pmc=3457779 |pmid=22239440}}</ref>|center
===PI3K-AKT-mTOR (PAM) pathway=== thumb|561x561px|Overview map of enzymes which compose and are impacted by the PI3K pathway<ref name=":15">{{Cite journal |last1=Singh |first1=Priyanka |last2=Kumar |first2=Veerandra |last3=Gupta |first3=Sonu Kumar |last4=Kumari |first4=Gudia |last5=Verma |first5=Malkhey |date=January 2021 |title=Combating TKI resistance in CML by inhibiting the PI3K/Akt/mTOR pathway in combination with TKIs: a review |url=http://link.springer.com/10.1007/s12032-021-01462-5 |journal=Medical Oncology |language=en |volume=38 |issue=1 |page=10 |doi=10.1007/s12032-021-01462-5 |pmid=33452624 |issn=1357-0560|url-access=subscription }}</ref> Associated with cell survival, growth and cell cycle, the PAM signalling pathway plays a central role in both CML, ALL, other leukemias and solid tumours, being found in around 50% of all cancers. Normally the PAM signalling pathway maintains and controls growth factors in all higher eukaryotic cells in response to external stimuli. Hyperactivation of this pathway therefore promotes pro-survival intracellular signalling via the PAM pathway, inducing drug resistance.<ref>{{Citation |last1=Kim |first1=Hye Na |title=PI3K Targeting in Non-solid Cancer |date=2022 |work=PI3K and AKT Isoforms in Immunity |volume=436 |pages=393–407 |editor-last=Dominguez-Villar |editor-first=Margarita |place=Cham |publisher=Springer International Publishing |language=en |doi=10.1007/978-3-031-06566-8_17 |isbn=978-3-031-06565-1 |pmc=10075235 |pmid=36243854 |last2=Ogana |first2=Heather |last3=Sanchez |first3=Vanessa |last4=Nichols |first4=Cydney |last5=Kim |first5=Yong-Mi}}</ref> In cancer cells, the PAM pathway gets stimulated by receptors like G-protein-coupled receptors (GPCR), and receptor tyrosine kinases (RTKs), among others. It is especially through the RTKs that cells with the ''BCR::ABL1'' fusion, the PAM pathway is activated. PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3). The phosphorylation of PIP2 to PIP3 activates AKT, which has numerous downstream signalling targets, related to cellular processes. Additionally, mTOR can act both upstream and downstream of AKT. Two multiprotein complexes of mTOR are involved in the PAM pathway, mTORC1 and mTORC2 which both regulate protein synthesis required for cell growth, angiogenesis, and proliferation. mTORC2 stimulates AKT activity, which in turn amplifies activity of mTORC1 by suppressing mTORC1 inhibitors. ''BCR::ABL1'' activation of the PAM pathway may additionally also occur by binding of two proteins, Crkl and c-Cbl, to the ABL fragment of the fusion oncoprotein. The BCR::ABL1 kinase protein will phosphorylate c-Cbl which will activate PI3K.<ref>{{Cite journal |last1=Glaviano |first1=Antonino |last2=Foo |first2=Aaron S. C. |last3=Lam |first3=Hiu Y. |last4=Yap |first4=Kenneth C. H. |last5=Jacot |first5=William |last6=Jones |first6=Robert H. |last7=Eng |first7=Huiyan |last8=Nair |first8=Madhumathy G. |last9=Makvandi |first9=Pooyan |last10=Geoerger |first10=Birgit |last11=Kulke |first11=Matthew H. |last12=Baird |first12=Richard D. |last13=Prabhu |first13=Jyothi S. |last14=Carbone |first14=Daniela |last15=Pecoraro |first15=Camilla |date=2023-08-18 |title=PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer |journal=Molecular Cancer |language=en |volume=22 |issue=1 |page=138 |doi=10.1186/s12943-023-01827-6 |doi-access=free |issn=1476-4598 |pmc=10436543 |pmid=37596643}}</ref><ref name=":15" />
===JAK-STAT pathway===
The JAK-STAT pathway is an evolutionary conserved signalling pathway involved over 50 cytokines and growth factors are associated with this pathway. Playing an important role in haematopoiesis, differentiation, immune modulation and apoptosis. In healthy cells, JAK proteins naturally phosphorylate each other, prompting a STAT protein to bind to the JAK tyrosine phosphorylated domain. The STAT protein is in turn itself phosphorylated by JAK. STAT is separated from JAK, followed by a translocation of STAT from the cytosol to the nucleus. In the nucleus STAT will induce transcriptional activation of specific genes and other downstream targets.<ref>{{Cite journal |last1=Liang |first1=Dong |last2=Wang |first2=Qiaoli |last3=Zhang |first3=Wenbiao |last4=Tang |first4=Hailin |last5=Song |first5=Cailu |last6=Yan |first6=Zhimin |last7=Liang |first7=Yang |last8=Wang |first8=Hua |date=2024-01-26 |title=JAK/STAT in leukemia: a clinical update |journal=Molecular Cancer |language=en |volume=23 |issue=1 |page=25 |doi=10.1186/s12943-023-01929-1 |doi-access=free |issn=1476-4598 |pmc=10811937 |pmid=38273387}}</ref> JAK2, STAT1, STAT3 and STAT5 have been shown to be constitutively active in CML models. Where JAK2 and STAT5 being the main components, where BCR::ABL1 enhances the JAK2-STAT5 pathway to enable oncogenic transformation. JAK2 has been shown to phosphorylate the Y177 domain on the BCR::ABL1 oncoprotein, which increases protein stability. JAK2 induces expression of the oncogene c-MYC, which is overexpressed in ''BCR::ABL1'' positive cells, and is a downstream target for activated JAK2 proteins in these cells. STAT 5 is crucial for development and survival of lymphoid leukemia cells, by regulating transcription of anti-apoptotic BCL proteins. c-MYC additionally enables the transactivation of the survivin promoter via JAK2-PI3K pathways, indicating a complex connection between these pathways. STAT5 is not essential for normal haematopoiesis, making it a good therapeutic target in ph+ leukemias.<ref name=":2" /><ref name=":16">{{Cite journal |last1=Amarante-Mendes |first1=Gustavo P. |last2=Rana |first2=Aamir |last3=Datoguia |first3=Tarcila Santos |last4=Hamerschlak |first4=Nelson |last5=Brumatti |first5=Gabriela |date=2022-01-17 |title=BCR-ABL1 Tyrosine Kinase Complex Signaling Transduction: Challenges to Overcome Resistance in Chronic Myeloid Leukemia |journal=Pharmaceutics |language=en |volume=14 |issue=1 |page=215 |doi=10.3390/pharmaceutics14010215 |doi-access=free |issn=1999-4923 |pmc=8780254 |pmid=35057108}}</ref>
===PP2A tumour suppressor gene –β-catenin pathway===
PP2A is a tumour-suppressor gene which constitutes 0,2% to 1% of total proteins found in mammalian cells, tasked with numerous processes, such as signal transduction, DNA replication, protein translation, regulating cell proliferation, cell cycle progression and differentiation. Studies have shown that in patients with the ''BCR::ABL1'' translocation, BCR::ABL1 fusion protein promotes loss of PP2A function; effectively turning off the tumour suppressor gene. The mechanism for this pathway, involving ''BCR::ABL1'', is complex, involving both the JAK/STAT pathway, and the Wnt/β-catenin pathway. The BCR::ABL1 tyrosine kinase will promote activation of JAK2, which in turn enhances β-catenin activity. β-catenin, a part of the Wnt/ β-catenin pathway associated with cancers unrelated directly to ''BCR::ABL1'', induces inactivation of PP2A via a protein called SET (also known as Inhibitor-2 of PP2A). SET acts as a potent inhibitor of PP2A, turning off PP2A's tumour suppressive activity. Counterintuitively, inhibition of PP2A has been shown to sensitize TKI-resistant cancer cells, making PP2A a target for therapies.<ref name=":16" /><ref>{{Cite journal |last1=Lai |first1=Damian |last2=Chen |first2=Min |last3=Su |first3=Jiechuang |last4=Liu |first4=Xiaohu |last5=Rothe |first5=Katharina |last6=Hu |first6=Kaiji |last7=Forrest |first7=Donna L. |last8=Eaves |first8=Connie J. |last9=Morin |first9=Gregg B. |last10=Jiang |first10=Xiaoyan |date=2018-02-07 |title=PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL + human leukemia |url=https://www.science.org/doi/10.1126/scitranslmed.aan8735 |journal=Science Translational Medicine |language=en |volume=10 |issue=427 |article-number=eaan8735 |doi=10.1126/scitranslmed.aan8735 |pmid=29437150 |issn=1946-6234|url-access=subscription }}</ref><ref>{{Cite journal |last1=Neviani |first1=Paolo |last2=Harb |first2=Jason G. |last3=Oaks |first3=Joshua J. |last4=Santhanam |first4=Ramasamy |last5=Walker |first5=Christopher J. |last6=Ellis |first6=Justin J. |last7=Ferenchak |first7=Gregory |last8=Dorrance |first8=Adrienne M. |last9=Paisie |first9=Carolyn A. |last10=Eiring |first10=Anna M. |last11=Ma |first11=Yihui |last12=Mao |first12=Hsiaoyin C. |last13=Zhang |first13=Bin |last14=Wunderlich |first14=Mark |last15=May |first15=Philippa C. |date=2013-10-01 |title=PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells |journal=Journal of Clinical Investigation |language=en |volume=123 |issue=10 |pages=4144–4157 |doi=10.1172/JCI68951 |issn=0021-9738 |pmc=3784537 |pmid=23999433}}</ref><ref>{{Cite journal |last1=Neviani |first1=Paolo |last2=Santhanam |first2=Ramasamy |last3=Trotta |first3=Rossana |last4=Notari |first4=Mario |last5=Blaser |first5=Bradley W. |last6=Liu |first6=Shujun |last7=Mao |first7=Hsiaoyin |last8=Chang |first8=Ji Suk |last9=Galietta |first9=Annamaria |last10=Uttam |first10=Ashwin |last11=Roy |first11=Denis C. |last12=Valtieri |first12=Mauro |last13=Bruner-Klisovic |first13=Rebecca |last14=Caligiuri |first14=Michael A. |last15=Bloomfield |first15=Clara D. |date=November 2005 |title=The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein |url=https://linkinghub.elsevier.com/retrieve/pii/S1535610805003363 |journal=Cancer Cell |language=en |volume=8 |issue=5 |pages=355–368 |doi=10.1016/j.ccr.2005.10.015|pmid=16286244 }}</ref>
===Apoptosis===
Programmed cell death, apoptosis, is controlled by several different mechanisms and pathways involving many enzymes and proteins. Disruption of these mechanisms can lead to loss of apoptotic function in a damaged cell, a hallmark characteristic of cancers. BCR::ABL1 encoded tyrosine kinase can impact both pro-apoptotic and anti-apoptotic proteins via different pathways. An important pro apoptotic is the p53 tumour suppressor, which reacts to DNA damage by inducing apoptosis. Related to p53 is p73, which encodes for multiple proteins through alternative splicing, and has a similar function to p53. Chemotherapeutic chemical cisplatin increases p73 levels in the cell, additionally cisplatin activates c-Abl tyrosine kinase, which enhances the pro-apoptotic ability of p73. c-Abl is activated by DNA damage, and regulates p73 through a c-Abl mechanism. BCR::ABL1 induces and MDM2 mRNA translation via a RNA binding protein. MDM2 negatively regulates p53 and p73 activity by targeting them for ubiquitination, a post translational process that recruits proteins to the proteasomes where they are degraded and recycled. Many chemotherapies are based on creating DNA damage to induce natural apoptosis, cancer cells with ''BCR::ABL1'' are therefore more resistant to these chemotherapies.<ref>{{Cite journal |last1=Trotta |first1=Rossana |last2=Vignudelli |first2=Tatiana |last3=Candini |first3=Olivia |last4=Intine |first4=Robert V. |last5=Pecorari |first5=Luisa |last6=Guerzoni |first6=Clara |last7=Santilli |first7=Giorgia |last8=Byrom |first8=Mike W. |last9=Goldoni |first9=Silvia |last10=Ford |first10=Lance P. |last11=Caligiuri |first11=Michael A. |last12=Maraia |first12=Richard J. |last13=Perrotti |first13=Danilo |last14=Calabretta |first14=Bruno |date=February 2003 |title=BCR/ABL activates mdm2 mRNA translation via the La antigen |url=https://linkinghub.elsevier.com/retrieve/pii/S1535610803000205 |journal=Cancer Cell |language=en |volume=3 |issue=2 |pages=145–160 |doi=10.1016/S1535-6108(03)00020-5|pmid=12620409 |hdl=11380/5392 |hdl-access=free }}</ref><ref name=":17">{{Cite journal |last1=Hao |first1=Qian |last2=Chen |first2=Jiaxiang |last3=Lu |first3=Hua |last4=Zhou |first4=Xiang |date=2023-03-29 |editor-last=Yao |editor-first=Xuebiao |title=The ARTS of p53-dependent mitochondrial apoptosis |journal=Journal of Molecular Cell Biology |language=en |volume=14 |issue=10 |article-number=mjac074 |doi=10.1093/jmcb/mjac074 |issn=1674-2788 |pmc=10053023 |pmid=36565718}}</ref><ref>{{Cite journal |last1=Gong |first1=JianGen |last2=Costanzo |first2=Antonio |last3=Yang |first3=Hong-Qiong |last4=Melino |first4=Gerry |last5=Kaelin |first5=William G. |last6=Levrero |first6=Massimo |last7=Wang |first7=Jean Y. J. |date=June 1999 |title=The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage |url=https://www.nature.com/articles/21690 |journal=Nature |language=en |volume=399 |issue=6738 |pages=806–809 |doi=10.1038/21690 |pmid=10391249 |bibcode=1999Natur.399..806G |issn=0028-0836|url-access=subscription }}</ref><ref>{{Cite journal |last1=Yuan |first1=Zhi-Min |last2=Shioya |first2=Hisashi |last3=Ishiko |first3=Takatoshi |last4=Sun |first4=Xiangao |last5=Gu |first5=Jijie |last6=Huang |first6=YinYin |last7=Lu |first7=Hua |last8=Kharbanda |first8=Surender |last9=Weichselbaum |first9=Ralph |last10=Kufe |first10=Donald |date=1999-06-24 |title=p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage |url=https://www.nature.com/articles/21704 |journal=Nature |language=en |volume=399 |issue=6738 |pages=814–817 |doi=10.1038/21704 |pmid=10391251 |bibcode=1999Natur.399..814Y |issn=0028-0836|url-access=subscription }}</ref> Other main pathway for apoptosis resistance in ''BCR::ABL1'' positive cancer cells is through the Bcl2 family of apoptotic regulatory proteins. BAD is a pro-apoptotic member of said protein family, when BAD is nonphosphorylated, it binds to the anti-apoptotic Bcl-X<sub>L</sub> and Bcl-2, promoting cell death. AKT and PI3K can phosphorylate BAD, preventing it from inhibiting anti-apoptotic Bcl-X<sub>L</sub> and Bcl-2, preventing cell death. AKT can also increase NF-κB activity by accelerating degradation of its inhibitor IκBα. This causes elevated Bcl-X<sub>L</sub> expression. The STAT5 pathway can also be involved, STAT5 can bind to the Bcl-x promoter, which increases expression of Bcl-X<sub>L</sub> further reinforcing resistance to apoptosis. Another pro-apoptotic is BAX, which plays a central role in mitochondria dependent apoptosis, is usually regulated by p53. In ''BCR::ABL1'' patients p53 is usually heavily downregulated, resulting in low to no activation of BAX. It is theorised that TKI activity can be enhanced by inhibition of Bcl-2, as Bcl-2 normally prevents apoptosis by binding and inhibiting BAD and BAX.<ref name=":17" /><ref>{{Cite journal |last1=Alam |first1=Manzar |last2=Alam |first2=Shoaib |last3=Shamsi |first3=Anas |last4=Adnan |first4=Mohd |last5=Elasbali |first5=Abdelbaset Mohamed |last6=Al-Soud |first6=Waleed Abu |last7=Alreshidi |first7=Mousa |last8=Hawsawi |first8=Yousef MohammedRabaa |last9=Tippana |first9=Anitha |last10=Pasupuleti |first10=Visweswara Rao |last11=Hassan |first11=Md. Imtaiyaz |date=2022-03-25 |title=Bax/Bcl-2 Cascade Is Regulated by the EGFR Pathway: Therapeutic Targeting of Non-Small Cell Lung Cancer |journal=Frontiers in Oncology |volume=12 |article-number=869672 |doi=10.3389/fonc.2022.869672 |doi-access=free |issn=2234-943X |pmc=8990771 |pmid=35402265}}</ref><ref>{{Cite journal |last1=Dumon |first1=S |last2=Santos |first2=S Constantino Rosa |last3=Debierre-Grockiego |first3=F |last4=Gouilleux-Gruart |first4=V |last5=Cocault |first5=L |last6=Boucheron |first6=C |last7=Mollat |first7=P |last8=Gisselbrecht |first8=S |last9=Gouilleux |first9=F |date=1999-07-22 |title=IL-3 dependent regulation of Bcl-xL gene expression by STAT5 in a bone marrow derived cell line |url=https://www.nature.com/articles/1202796 |journal=Oncogene |language=en |volume=18 |issue=29 |pages=4191–4199 |doi=10.1038/sj.onc.1202796 |pmid=10435632 |issn=0950-9232}}</ref><ref>{{Cite journal |last1=Koo |first1=Nayeong |last2=Sharma |first2=Arun K. |last3=Narayan |first3=Satya |date=2022-04-30 |title=Therapeutics Targeting p53-MDM2 Interaction to Induce Cancer Cell Death |journal=International Journal of Molecular Sciences |language=en |volume=23 |issue=9 |page=5005 |doi=10.3390/ijms23095005 |doi-access=free |issn=1422-0067 |pmc=9103871 |pmid=35563397}}</ref><ref>{{Cite journal |last=Fernandez-Luna |first=J. L. |date=2000 |title=Bcr-Abl and inhibition of apoptosis in chronic myelogenous leukemia cells |url=http://link.springer.com/10.1023/A:1009623222534 |journal=Apoptosis |volume=5 |issue=4 |pages=315–318 |doi=10.1023/A:1009623222534|pmid=11227211 |url-access=subscription }}</ref> All of these mechanisms attribute to the cell survival and drug resistance which is so characteristic for CML and ALL.<ref name=":2" />
== Nomenclature == {| class="wikitable" !Nomenclature !Definition |- |BCR |Breakpoint Cluster Region |- |ABL1 |Abelson Tyrosine Kinase 1 |- |Ph+ |Philadelphia chromosome positive |- |Ph-like |Similar gene expression profile to Ph+ |- |'''t(9;22)(q34;q11)''' | |- |t |translocation |- |(9;22) |exchange between chromosomes 9 and 22 |- |q34 |ABL1 gene on chromosome 9 |- |q11.2 |BCR gene on chromosome 22 |} ''Table 1. Philadelphia chromosome nomenclature defined by the BCR-ABL1 fusion gene, from a translocation between chromosomes 9 and 22 t(9;22)(q34;q11)''<ref>{{Cite journal |last1=Aboul-Soud |first1=Mourad A. M. |last2=Alzahrani |first2=Alhussain J. |last3=Mahmoud |first3=Amer |date=2021-01-01 |title=Decoding variants in drug-metabolizing enzymes and transporters in solid tumor patients by whole-exome sequencing |journal=Saudi Journal of Biological Sciences |volume=28 |issue=1 |pages=628–634 |doi=10.1016/j.sjbs.2020.10.052 |issn=1319-562X |pmc=7783809 |pmid=33424349|bibcode=2021SJBS...28..628A }}</ref><ref name=":2" /><ref name=":3">{{Cite journal |last1=Sattler |first1=Martin |last2=Griffin |first2=James D. |date=2001-04-01 |title=Mechanisms of Transformation by the BCR/ABL Oncogene |url=https://link.springer.com/article/10.1007/BF02981952 |journal=International Journal of Hematology |language=en |volume=73 |issue=3 |pages=278–291 |doi=10.1007/BF02981952 |pmid=11345193 |issn=1865-3774|url-access=subscription }}</ref>''.''
{| class="wikitable" !Ph Type !Protein Size !Disease Association |- |P210 BCR-ABL1 |210 kDa |Classical CML, Ph+ ALL (~30%) |- |P190 BCR-ABL1 |190 kDa |Ph+ ALL (~70%), rare in CML |- |P230 BCR-ABL1 |230 kDa |Chronic Neutrophilic Leukemia (CNL), rare CML variant |} ''Table 2. The size and disease association of the different BCR-ABL1 fusion proteins based on the breakpoints in the BCR and ABL1 genes''<ref name=":3" />''.''
==Therapy== The primary objective of Ph+ CML and ALL treatment is to improve survival rates to match the general population. A secondary objective, although achieved in fewer patients, is a deep molecular response (DMR), which can allow treatment discontinuation and lead to a treatment-free remission.<ref name=":4">{{Cite journal |last1=Senapati |first1=Jayastu |last2=Sasaki |first2=Koji |last3=Issa |first3=Ghayas C. |last4=Lipton |first4=Jeffrey H. |last5=Radich |first5=Jerald P. |last6=Jabbour |first6=Elias |last7=Kantarjian |first7=Hagop M. |date=2023-04-24 |title=Management of chronic myeloid leukemia in 2023 – common ground and common sense |journal=Blood Cancer Journal |language=en |volume=13 |issue=1 |page=58 |doi=10.1038/s41408-023-00823-9 |issn=2044-5385 |pmc=10123066 |pmid=37088793}}</ref>
The main treatment options for Ph+ leukemias are Tyrosine kinase inhibitors (TKIs), chemotherapy, often in combination with TKIs, and allogeneic treatments such as stem cell transplantation (HSCT). Chemotherapy is often used before stem cell transplantation in high-risk patients. HSCT is used for younger or high-risk patients who don't respond well to TKIs.<ref name=":4" /><ref name=":5">{{Cite journal |last1=Foà |first1=Robin |last2=Chiaretti |first2=Sabina |date=2022-06-22 |title=Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia |url=https://www.nejm.org/doi/10.1056/NEJMra2113347 |journal=New England Journal of Medicine |volume=386 |issue=25 |pages=2399–2411 |doi=10.1056/NEJMra2113347 |pmid=35731654 |issn=0028-4793|url-access=subscription }}</ref>
=== Tyrosine kinase inhibitors (TKIs) === thumb|464x464px|Structural features of the Abl kinase domain important for activity and inhibitor binding. A) first generation TKI imatinib, B) second generation TKI dasatinib<ref>{{Cite journal |last1=Panjarian |first1=Shoghag |last2=Iacob |first2=Roxana E. |last3=Chen |first3=Shugui |last4=Engen |first4=John R. |last5=Smithgall |first5=Thomas E. |date=2013-02-22 |title=Structure and Dynamic Regulation of Abl Kinases* |journal=Journal of Biological Chemistry |language=English |volume=288 |issue=8 |pages=5443–5450 |doi=10.1074/jbc.R112.438382 |doi-access=free |issn=0021-9258 |pmc=3581414 |pmid=23316053}}</ref> The BCR-ABL fusion gene produces an abnormal tyrosine kinase that drives Ph+ leukemia. TKIs target the BRC-ABL1 fusion protein and block the abnormal tyrosine kinase activity, preventing uncontrolled cell proliferation.<ref name=":9">{{Cite journal |last1=Komorowski |first1=Lukasz |last2=Fidyt |first2=Klaudyna |last3=Patkowska |first3=Elżbieta |last4=Firczuk |first4=Malgorzata |date=2020-08-12 |title=Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities |journal=International Journal of Molecular Sciences |language=en |volume=21 |issue=16 |page=5776 |doi=10.3390/ijms21165776 |doi-access=free |issn=1422-0067 |pmc=7460962 |pmid=32806528}}</ref> The first TKI (imatinib) was approved in the US in 2001; since then, 5 additional ''BCR::ABL1'' TKIs have been approved by the US food and drug administration (FDA).<ref name=":6">{{Cite journal |last1=Jabbour |first1=Elias |last2=Kantarjian |first2=Hagop |date=2025-03-17 |title=Chronic Myeloid Leukemia: A Review |url=https://jamanetwork.com/journals/jama/article-abstract/2831659 |journal=JAMA |volume=333 |issue=18 |pages=1618–1629 |doi=10.1001/jama.2025.0220 |pmid=40094679 |issn=0098-7484|url-access=subscription }}</ref> The TKIs are categorized in generations pertaining to potency, whereas each subsequent generation is effective to mutations with resistance to the previous generation.<ref name=":4" /><ref name=":6" /> {| class="wikitable" !BCR::ABL1 TKI !Generation |- |Imatinib |First-generation |- |Dasatinib, Nilotinib, Bosutinib |Second-generation |- |Ponatinib, Asciminib |Third-generation |} ''Table 3. FDA approved BCR::ABL1 TKIs categorized by generation''<ref name=":6" />''.''
The introduction of TKIs was initially alongside chemotherapy. Prior to TKIs, chemotherapy had been the standard treatment for Ph-positive leukemia with limited success and low long-term survival rates.<ref name=":6" /> The combination improved survival rates resulted in more patients achieving hematologic remission, where leukemia cells can no longer be detected in the blood. However, this approach had significant side effects, with some patients dying from complications during early phases of treatment.<ref name=":5" /> Further research explored the use of TKIs with reduced-intensity chemotherapy and since 2004, clinical trials in Italy have used TKIs without chemotherapy during the first phase of treatment. This approach led to higher remission rates, fewer complications and eligibility for elderly patients unable to tolerate intense chemotherapy.<ref name=":5" /> Tyrosine kinase inhibitors are now a standard first line therapy for Ph positive ALL and CML.<ref name="Jabbour 2025">{{cite journal |last1=Jabbour |first1=Elias |last2=Kantarjian |first2=Hagop |title=Chronic Myeloid Leukemia: A Review |journal=JAMA |date=13 May 2025 |volume=333 |issue=18 |pages=1618–1629 |doi=10.1001/jama.2025.0220 |pmid=40094679 }}</ref><ref name="Foa 2025">{{cite journal |last1=Foà |first1=Robin |title=Ph-Positive Acute Lymphoblastic Leukemia — 25 Years of Progress |journal=New England Journal of Medicine |date=15 May 2025 |volume=392 |issue=19 |pages=1941–1952 |doi=10.1056/NEJMra2405573 |pmid=40367376 }}</ref> ALL was once the deadliest hematologic cancer, but since the introduction of TKIs in the early 2000s, long term survival is greater than 60% and TKIs are associated with 94-100% complete response rates and 30-40% molecular response rates.<ref name="Foa 2025"/> TKIs are usually used with a low dose of chemotherapy for induction therapy for Ph positive ALL, but clinical trials have shown that long term remission can be achieved with TKIs alone, sparing the person potentially toxic chemotherapy.<ref name="Foa 2025"/> Blinatumomab a CD19 monoclonal antibody (with CD19 present on B-lineage ALL cells) may be used in relapsed or refractory Ph positive ALL. Blinatumomab activates CD19 on T cells and activates them to attack leukemic B cells.<ref name="Foa 2025"/> When combined with TKIs it is associated with greater hematologic response and greater survival; an overall survival of 95% at 18 months and 88% disease free survival.<ref name="Foa 2025"/>
=== Allogeneic transplantation and immunotherapy === Based on the patient's condition and response to TKIs, other treatment options such as Allogeneic Stem Cell Transplantation (HSCT) or immunotherapy. HSCT is primarily considered for younger patients or high-risk patients that do not respond well to TKIs. The process involves transplanting bone marrow stem cells from a matched donor and is infrequently used to treat CML due to long-term complications and risk factors.<ref name=":5" /><ref name=":6" /> Traditionally Allogeneic transplantation has been the standard curative treatment for Ph+ leukemia however, studies suggest it may not improve survival in patients without minimal residual disease (MRD). Immunotherapies are often considered in MRD cases or in instances of relapsed patients. Third generation, more potent TKIs and immunotherapies, may lead to fewer patients requiring transplantation as standard treatment. For patients with persistent MRD, TKI resistant mutations or multiple relapses, HSCT should be considered.<ref name=":5" /> Depending on the stage of CML, cure rates with HSCT range from 20% to 60%. Improved techniques have reduced relapse free mortality rates after transplant to ~12% after 5 years and has made HSCT feasible for older patients.<ref name=":6" /> Post-transplant, TKI maintenance therapy is recommended.<ref name=":5" />
==Prognosis== The introduction of BCR::ABL1 targeting TKIs significantly improved Ph+ CML prognosis. TKIs have increased the 10-year overall survival rate from less than 20% to 80%-85%. This has resulted in a similar 10-year relative survival rate for patients with CML and age-matched CML negative controls.<ref name=":6" />
==History== The Philadelphia chromosome was co-discovered in 1960 by David Hungerford and Peter Nowell, cytogeneticists<ref>{{Cite journal |last=Ortiz-Hidalgo |first=Carlos |date=2025-03-19 |title=History of Leukemia, Revisited |url=https://link.springer.com/article/10.1007/s11912-025-01658-2 |journal=Current Oncology Reports |volume=27 |issue=4 |pages=472–482 |language=en |doi=10.1007/s11912-025-01658-2 |pmid=40106215 |issn=1534-6269|url-access=subscription }}</ref><ref>{{Cite journal |last1=Rudkin |first1=George T. |last2=Hungerford |first2=David A. |last3=Nowell |first3=Peter C. |date=1964-06-05 |title=DNA Contents of Chromosome Ph1 and Chromosome 21 in Human Chronic Granulocytic Leukemia |url=https://www.science.org/doi/10.1126/science.144.3623.1229 |journal=Science |volume=144 |issue=3623 |pages=1229–1232 |doi=10.1126/science.144.3623.1229|pmid=14150328 |url-access=subscription }}</ref> at the University of Pennsylvania School of Medicine. Through an accident,{{explain|date=August 2025}} Nowell managed to clearly see metaphase spreads in leukemic cells, and he and Hungerford subsequently described an unusual, small chromosome present in leukocytes from patients with CML.<ref name=":7">{{Cite journal |last1=Chandra |first1=H. Sharat |last2=Heisterkamp |first2=Nora C. |last3=Hungerford |first3=Alice |last4=Morrissette |first4=Jennifer J. D. |last5=Nowell |first5=Peter C. |last6=Rowley |first6=Janet D. |last7=Testa |first7=Joseph R. |date=2011-04-01 |title=Philadelphia Chromosome Symposium: commemoration of the 50th anniversary of the discovery of the Ph chromosome |journal=Cancer Genetics |volume=204 |issue=4 |pages=171–179 |doi=10.1016/j.cancergen.2011.03.002 |issn=2210-7762 |pmc=3092778 |pmid=21536234}}</ref><ref name=":8">{{Cite journal |last=Koretzky |first=Gary A. |date=2007-08-01 |title=The legacy of the Philadelphia chromosome |journal=The Journal of Clinical Investigation |language=en |volume=117 |issue=8 |pages=2030–2032 |doi=10.1172/JCI33032 |issn=0021-9738 |pmc=1934583 |pmid=17671635}}</ref> This finding provided strong evidence supporting Boveri's hypothesis that a single genetic alteration could drive cancer development. While no other consistent chromosomal abnormalities were initially found in leukemias, the discovery of the Philadelphia chromosome marked a breakthrough in understanding cancer genetics.<ref>{{Cite journal |last=Nowell |first=Peter C. |date=2007-08-01 |title=Discovery of the Philadelphia chromosome: a personal perspective |journal=The Journal of Clinical Investigation |language=en |volume=117 |issue=8 |pages=2033��2035 |doi=10.1172/JCI31771 |issn=0021-9738 |pmc=1934591 |pmid=17671636}}</ref>
The mechanism for which the Philadelphia chromosome arises as a translocation, not a deletion was discovered by Janet Rowley in 1972, and subsequent paper was published in 1973. Rowley used Giemsa staining and quinacrine banding to show that the Ph chromosome resulted from a translocation between chromosomes 9 and 22. The presence of the t(9;22) translocation in nearly all bone marrow cells from CML patients implied that the abnormality was involved as a cause and not a result of the cancer.<ref name=":7" /><ref name=":8" />
In 1984, Nora Heisterkamp and John Groffen later mapped the breakpoints on chromosomes 9 and 22, identifying the BCR on chromosome 22 and its fusion with the ABL gene from chromosome 9.<ref>{{Cite journal |last1=Groffen |first1=John |last2=Stephenson |first2=John R. |last3=Heisterkamp |first3=Nora |last4=Klein |first4=Annelies de |last5=Bartram |first5=Claus R. |last6=Grosveld |first6=Gerard |date=1984-01-01 |title=Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22 |url=https://linkinghub.elsevier.com/retrieve/pii/0092867484900771 |journal=Cell |language=English |volume=36 |issue=1 |pages=93–99 |doi=10.1016/0092-8674(84)90077-1 |pmid=6319012 |issn=0092-8674|url-access=subscription }}</ref> Owen Witte's work demonstrated that the abnormal tyrosine kinase produced by BRC-ABL fusion gene had enhanced kinase activity. Experiments introducing the BCR-ABL gene in mice led to CML-like disease, proving its central role in leukemia development.<ref name=":7" />
==Notes==
Many of the sources used in this article refer to different statistics. For example, frequencies of the P190, P210 and P230 oncoproteins in CML and ph+ B-ALL. In this article, the % frequencies were set at an average value based on information from different sources. This discrepancy can probably be attributed to the fact that the review articles used here were based on different studies where frequencies were determined from populations used in the study. Random variations in detected frequency could therefore be to blame for this discrepancy.
Apart from the RAS-RAF, PI3K-AKT and JAK/STAT pathways, a certain source mentioned an additional pathway, the WNT/β-Catenin Pathway, that could also be involved in BCR::ABL1 related cancers. This was however excluded from this article, with exception to its part in the PP2A, due to a lack of good sources supporting this.
== See also == * Chronic myelogenous leukemia * Acute lymphocytic leukemia
==References== {{reflist}}
=== General Interest === {{cite book | last=Wapner | first=Jessica | title=The Philadelphia Chromosome: A Mutant Gene and the Quest to Cure Cancer at the Genetic Level| publisher=The Experiment | date=2014 | isbn=978-1-61519-197-0 }}
== External links == {{Medical resources | DiseasesDB = | ICD10 = {{ICD10|C|92|1|c|81}} | ICD9 = {{ICD9|205.1}} | ICDO = 9875/3 | OMIM = | MedlinePlus = | eMedicineSubj = | eMedicineTopic = | MeshID = D010677 }} * {{MeshName|Philadelphia+chromosome}} * {{MeshName|bcr-abl+Fusion+Proteins}}
{{Chromosomal abnormalities}} {{Myeloid malignancy|us=y}}
Category:Chromosomal translocations