BCR – Acute Lymphoblastic Leukemia

Philadelphia chromosome-positive acute lymphoblastic leukemia is characterized by the somatic t(9;22)(q34;q11) translocation, resulting in the BCR-ABL1 fusion oncogene. In childhood ALL, the Philadelphia chromosome occurs in approximately 2–5% of newly diagnosed cases, correlating with poor prognosis (PMID:9760154). Both the major breakpoint cluster region (Mbcr) and minor breakpoint (m-bcr) generate p210 and p190 fusion proteins, respectively, with p190 predominating in Ph-positive ALL (PMID:10640143).

The disease arises from a somatic event; there is no germline inheritance identified. No segregation of this fusion has been observed in familial studies, consistent with its role as an acquired leukemogenic driver.

Genetic evidence includes multiple independent case series and cohort studies detecting BCR-ABL1 transcripts by RT-PCR and FISH in over 50 unrelated ALL patients across five reports. Complex rearrangements such as dicentric dic(7;9)(p11;p11) with coexistent t(9;22) have been described in 7 patients, supporting a recurrent cytogenetic subgroup in B-ALL (PMID:16938575). Pediatric ALL studies identified three kinase domain mutations—E255V, D276G, and F317L—in relapsed cases under tyrosine kinase inhibitor therapy, highlighting clonal evolution (PMID:25895602).

Variant spectrum comprises the fusogenic c.1060T>G (p.Ser354Ala) mutation in BCR affecting serine-threonine kinase activity, disrupting Bcr-Abl regulation (PMID:11809685). Fusion transcripts include b2a2 and e1a2 junctions encoding p210 and p190 proteins.

Functional assays demonstrate that Bcr-Abl has constitutive tyrosine kinase activity essential for leukemogenesis. Phosphorylation mapping identified key residues Y-360 and Y-283 modulating Bcr kinase inhibition by Abl, and Ser-354 phosphorylation of Bcr is required for downregulation of Bcr-Abl activity in vitro (PMID:8622703; PMID:11809685). Mouse and cellular models of BCR-FGFR1 fusions further underscore a critical role for Bcr domains in transformation.

No significant conflicting evidence disputes the role of BCR-ABL1 in Ph-positive ALL. Rare cases of chronic myeloid leukemia expressing p190 did not present with ALL, indicating that additional factors influence disease phenotype (PMID:8756076).

Integration of genetic and experimental data confirms that BCR-ABL1 fusions are a definitive and actionable biomarker in Ph-positive ALL. Tyrosine kinase inhibitors targeting Bcr-Abl are central to clinical management. Key take-home: Detection of BCR-ABL1 by RT-PCR or FISH is critical for diagnosis, risk stratification, and targeted therapy in Ph-positive acute lymphoblastic leukemia.

References

• Annals of Hematology • 1998 • Molecular detection of a late-appearing BCR-ABL gene in a child with T-cell acute lymphoblastic leukemia. PMID:9760154
• Cancer Genetics and Cytogenetics • 2000 • Complex chromosome 9, 20, and 22 rearrangements in acute lymphoblastic leukemia with duplication of BCR and ABL sequences. PMID:10640143
• Cancer Genetics and Cytogenetics • 2006 • Dicentric (7;9)(p11;p11) is a rare but recurrent abnormality in acute lymphoblastic leukemia: a study of 7 cases. PMID:16938575
• Acta Haematologica • 2015 • Emerging BCR/ABL1 Mutations Under Treatment with Tyrosine Kinase Inhibitors in Paediatric Acute Lymphoblastic Leukaemia. PMID:25895602
• Molecular and Cellular Biology • 1996 • Inhibition of Bcr serine kinase by tyrosine phosphorylation. PMID:8622703
• Cancer Research • 2002 • Inhibition of the Bcr-Abl oncoprotein by Bcr requires phosphoserine 354. PMID:11809685
• American Journal of Hematology • 1996 • Unusual expression of mRNA typical of Philadelphia positive acute lymphoblastic leukemia detected in chronic myeloid leukemia. PMID:8756076

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