BCR – Acute Myeloid Leukemia

Multiple independent case reports have identified somatic rearrangements of the breakpoint cluster region gene (BCR) in acute myeloid leukemia (AML), most commonly as BCR::ABL1 fusions arising via t(9;22)(q34;q11.2). Five unrelated AML patients have been described with BCR–ABL rearrangements or variant fusions including BCR–JAK2, each confirmed by cytogenetics and molecular assays ([PMID:10049047]; [PMID:7950925]; [PMID:22549126]; [PMID:36307214]; [PMID:8330271]). These cases underscore the oncogenic role of BCR fusion proteins in driving myeloid transformation, although no familial segregation has been observed.

BCR encodes a dual-function protein with a Rho GTPase-activating (GAP) domain and a serine/threonine kinase domain. Mutational analyses of the GAP domain have delineated critical residues for Rac1 binding and GTPase activation, and studies of BCR–ABL serine/threonine kinase inhibition implicate dysregulated phosphorylation in leukemogenesis ([PMID:8021274]). Despite these insights, functional modeling in AML-specific systems remains limited.

Key take‐home: Somatic BCR fusions comprise a rare but clinically actionable subset of AML, warranting inclusion in targeted diagnostic panels.

References

• Cancer genetics and cytogenetics • 1993 • Deletion of chromosome 22 without bcr rearrangement and without juxtaposition of c-abl in a case of acute myeloid leukemia. PMID:8330271
• Leukemia • 1999 • Clonally unrelated BCR-ABL-negative acute myeloblastic leukemia masquerading as blast crisis after busulphan and interferon therapy for BCR-ABL-positive chronic myeloid leukemia. PMID:10049047
• Leukemia & lymphoma • 1994 • A Ph+ acute myeloid leukaemia expressing both CML-type and ALL-type BCR/ABL mRNA transcripts. PMID:7950925
• Molecular cytogenetics • 2012 • BCR-JAK2 fusion as a result of a translocation (9;22)(p24;q11.2) in a patient with CML-like myeloproliferative disease. PMID:22549126
• Cold Spring Harbor molecular case studies • 2022 • Comprehensive molecular characterization of a rare case of Philadelphia chromosome-positive acute myeloid leukemia. PMID:36307214
• The Journal of biological chemistry • 1994 • Breakpoint cluster region gene product-related domain of n-chimaerin. Discrimination between Rac-binding and GTPase-activating residues by mutational analysis. PMID:8021274

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