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Genetics, Philadelphia Chromosome

Editor: Faiz Anwer Updated: 7/17/2023 8:44:41 PM


Philadelphia chromosome (Ph), named after the city where it was first described, was described for the first time by Nowell and Hungerford in 1960, in two patients who had lost the long arm of chromosome 22.[1][2][3] As the Giemsa staining improved over the decade, Rowley showed that this truncated chromosome was generated as a result of the translocation of the long arm of chromosomes 9 and 22.[2][3][4] The presence of the abnormal Ph chromosome in cells of myeloid, megakaryocytic, along with erythroid lineages pointed to the origination of the disorder in a pluripotential stem cell.[2] Philadelphia chromosome is the hallmark of chronic myeloid leukemia (CML) along with some other leukemias including acute lymphoblastic leukemia (ALL) (mostly B cell ALL, rarely T cell ALL), acute myeloid leukemia (AML), chronic neutrophilic leukemia (CNL), and mixed phenotype acute leukemia (MPAL).[4][5][6][7][8][9][10][11]


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The Philadelphia chromosome is generated when the proto-oncogene Abelson murine leukemia (ABL1)  gene, located on the band q34 on chromosome 9, translocates to the band q11 on chromosome 22 where the breakpoint cluster gene (BCR) is.[8][12] The translocation t(9;22)(q34;q11) results in the formation of a fusion gene called BCR-ABL1.[4]


The domains from BCR include:

  1. CC domain
  2. Ser/Thr kinase domain (contains a docking site Y177)
  3. Rho/GEF kinase domain

The domains from ABL1 include:

  1. SH domain (SH1/SH2)
  2. Proline-rich domain
  3. DNA & actin-binding domains

The CC domain and Y177 of BCR are essential for the activation of the ABL1 gene and have shown to be closely associated with sensitivity to tyrosine kinase inhibitor (TKI). The Rho/GEF kinase domain plays a vital role in activating differentiation in the protooncogene induced leukemogenesis.[4][13]

The SH domain of ABL1 controls the gene’s activation and deactivation, and hence this domain is an important site for pharmacologic intervention.[4]

As a result of different breakpoints in the BCR gene, that occur over quite a short DNA stretch of 5 -6 kilobases in the middle of the gene, three different BCR/ABL1 proteins are formed namely P190, P210, P230 which are usually associated with ALL, CML and CNL respectively. The numeral value represents the kDa size of the hybrid protein. There have been some reports showing correlations of P190 with CML, P210 with ALL, and P190 or P210 with AML. P230is formed by the fusion of the ABL1 gene with almost the entire BCR gene leading to the production of a 230-kDa protein.[2] It is the molecular diagnostic marker for neutrophilic-chronic myeloid leukemia (CML-N).[4][9]  

In CML, the oncoprotein P210 forms by the fusion of exon 2 (b2) or exon 3 (b3) of the BCR gene with the exon 2 (a2) of the ABL1 gene leading to the formation of either b2a2 or b3a2 11345193. Both of the transcripts produce a hybrid P210.[4] 


The normal ABL Tyrosine Kinase (TK) is responsible for the activation of signal pathways that lead to increased proliferation, better viability, and changed migration as well as homing. Normally these pathways are under close regulation by different hematopoietic growth factors.[2] The ABL1 protein is a non-receptor tyrosine kinase, and it exists throughout the hematopoietic development, however myeloid maturation results in its declining levels.[4] The normal BCR gene is responsible for the oxidative burst in neutrophils.


The generation of BCR/ABL1 results in the constitutive activation of tyrosine kinase. It results in continued cell proliferation, inhibiting cell differentiation, and cell death. There are numerous pathways associated with the pathogenesis of BCR-ABL1 gene, including:

  • JAK2/STAT pathway: The activation of Janus Kinase (JAK) and Signal Transducers and Activation of Transcription (STAT) has been reported in P190 and P210positive leukemias. The JAK2/STAT activation in BCR/ABL1 leads to uncontrolled cell growth as well as cell survival.[14][15][16]
  • PI3K-AKT-mTOR pathway: The PI3K-AKT-mammalian target of the rapamycin (mTOR) pathway activates the c-kit positive hematopoietic stem cells; this leads to a proliferative state in CML.[17] This pathway controls cell survival, proliferation, cell cycle arrest, and has gained importance for pharmacological intervention over the past decade.[4]
  • MAPK/ERK (RAS/RAF/MEK/ERK) pathway: This pathway is involved in signal transmission from cell surface receptors to nuclear factors involved in transcription. Osteopontin (OPN), which overexpresses in BCR/ABL1, uses this pathway to maintain a leukemic microenvironment. It, in turn, promotes and maintains the proliferation and survival of leukemic cells as well as plays a role in cell differentiation and apoptosis.[4][18] 
  • TRAIL-induced apoptosis: Tumor necrosis factor (TNF)- related apoptosis-inducing ligand- TNFSF10 (TRAIL) is a death receptor ligand that normally plays a role in apoptosis. BCR/ABL1 oncogene results in the downregulation of TRAIL, hence leading to decreased apoptosis.[19][20][21][20]
  • C/EBP -mediated differentiation: CCAAT/enhancer-binding proteins (C/EBPs) are a type of transcription factors that are involved in the regulation of normal maturation of common myeloid cells to granulocyte-monocyte progenitor cells. This pathway is suppressed by the BCR/ABL1 oncogene.[4][22]


In addition to the leukemogenic effect, evidence suggests that BCR/ABL1 oncogene independently leads to genomic instability.[23] A recent study has shown that several genes that predominantly play a role in the proliferation and differentiation of hematopoietic stem cells are upregulated in BCR/ABL positive CML.[24]

Common genes that are reportedly deleted in Philadelphia positive leukemias include

  • IKZF1 (7q12.2) [25]        
  • PAX5 (9p13) [26]
  • EBF1 (5q34)  [27]
  • CDKN2A/B (9p13-p23.1) [28]
  • IG (14q32.33) [28]
  • TCR (14q11.2) [28]
  • BTG1 (12q21.33) [29]

Studies have shown that primary or acquired resistance to treatment as well as relapse, can be attributed to different mutations. Rearrangements in the BCR gene can help in the prediction of response to therapy.[4]


Philadelphia chromosome is detectable with cytogenetic testing, or a reverse transcriptase PCR test can demonstrate the BCR/ABL transcripts.[2] Along with a quantitative PCR for BCR/ABL1, flow cytometry is also necessary to determine the lineage. As mentioned before, the patients usually have a concurrent genetic abnormality, so it is reasonable to get a mutational analysis done.[30][31] In addition to the above testing, liver function tests, as well as renal function tests, should be performed.[30]


This oncogene leads to constitutive activation of tyrosine kinase, which is responsible for more proliferation and better viability of the myeloid lineage cells.[4] The translocation results in decreased requirements for growth factors and provides freedom from their regulatory control.[2] This oncogene also affects cellular differentiation and apoptosis.[4]

Clinical Significance

In addition to CML, Philadelphia chromosome has shown an association with different leukemias including

  • Acute Myeloid Leukemia (AML) [4][5]
  • Acute Lymphoblastic Leukemia (ALL)  (mostly B cell ALL, rarely T cell ALL) [6][7][8]
  • Chronic Neutrophilic Leukemia (CNL) [9]
  • Mixed Phenotype Acute Leukemia (MPAL) [10]  

There have been reports of detection of the chromosomal abnormality rarely in normal healthy people.[2] Recently, a Philadelphia like ALL (Ph-like ALL) has been identified, which lacks the novel BCR-ABL1 translocation.[32]

CML: The Ph chromosome is the diagnostic feature of CML. CML has an incidence of 50 per million per year and accounts for approximately 7 to 15% of the leukemias in the adult population.[2][33] 

ALL: Philadelphia chromosome has been detected in 11 to 29 % of patients with ALL, although it is rarer with a prevalence of 1 to 3% in childhood ALL.[34][35]

AML: In patients with AML, the chromosomal abnormality has a reported incidence of less than 1.5%.[36]

MPAL: Data collected from patients diagnosed with MPAL shows that the Ph chromosome is the most frequent aberrant cytogenetic abnormality, which has led to the recognition of Ph+MPAL as a distinct disease entity with a prevalence of less than 1% of all acute leukemias.[37]


For CML, at the moment, many (five FDA approved) tyrosine kinase inhibitors, belonging to different generations, (TKI) are being used for the treatment. TKIs belonging to different generations are currently available. Frist generation TKI includes imatinib, and second-generation TKI includes bosutinib, dasatinib, and nilotinib. Third generation TKIs include ponatinib. For the chronic phase, TKI first and second-generation TKIs are included in the frontline treatments recommended.[30][38][39][40][41]

In patients diagnosed with the chronic phase of CML, risk calculations are performed before initiation of therapy. For this purpose, two different scoring systems are used.[31] One is the Sokal risk calculation, which requires the age of the patient, platelet count, the percentage of myeloblasts found in the peripheral blood and size of the spleen, whereas the Hasford risk calculation utilizes the same variables as Sokal calculator except for the percentage of myeloblasts it uses the percentage of blasts, basophils, and eosinophils.[42][43][42] For patients that have an intermediate or higher risk score, the recommendation is to consider the second-generation TKIs as the first line.[30][40][41]

For patients with treatment failure or resistance to prior lines, the third generation TKI should be used.[44] For patients with a disease that is refractory to the TKI therapy, a chemotherapeutic agent omacetaxine is also a recommendation.[30][45] Studies have shown that primary or acquired resistance to treatment, as well as relapse, is attributable to different mutations. Rearrangements in the BCR gene can help in the prediction of response to therapy.

For patients with Ph+ive ALL, in addition to TKI, concurrent use of chemotherapeutic agents has shown remarkable results. For patients who are refractory to the TKI therapy and for patients with Ph+ive MPAL, a combination of alternative or advanced generation TKIs, and hematopoietic stem cell transplantation are recommendations.[4]


The status of the Philadelphia chromosome is associated with substantially different prognoses in patients of different leukemic phenotypes. The presence of the Ph chromosome has also correlated with a higher risk of concurrent genomic abnormalities.[4]

In patients of CML, the location of the breakpoint in the BCR gene has shown an important association with prognosis. CML patients with a double Philadelphia chromosome are associated with a worse prognosis than those with a single Philadelphia chromosome.[46] The presence of concurrent genetic abnormalities is associated with a worse prognosis than in the blastic phase of CML.[2]

ALL patients, both adults, as well as children who are Ph+ive, have shown a poor prognosis in comparison to those who are Ph -ive.[8]

Patients with Ph+ive MPAL have shown a worse outcome in comparison to other leukemic phenotypes.[4]



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