BCRABL

BCR-ABL refers to the fusion gene created by the BCR and ABL1 genes, whose product is a constitutively active tyrosine kinase implicated in certain leukemias. It arises from the reciprocal translocation t(9;22)(q34;q11), which generates the Philadelphia chromosome. The resulting BCR-ABL fusion oncoprotein drives leukemogenesis by continuously activating signaling pathways that promote cell proliferation and survival, including RAS/MAPK, PI3K/AKT, and STAT signaling.

Different BCR-ABL transcripts produce proteins of varying size. The most common in chronic myeloid leukemia (CML) are p210, arising from the e13a2 (b2a2) or e14a2 (b3a2) transcripts, while p190 is more typical of a subset of acute lymphoblastic leukemia (ALL) cases. The BCR portion contributes dimerization domains that enhance kinase activity, reinforcing oncogenic signaling.

Clinical significance and diagnosis: BCR-ABL is present in the majority of CML cases and in a subset of ALL, particularly adults. Diagnosis is achieved by detecting BCR-ABL transcripts with RT-PCR, identifying the Philadelphia chromosome by karyotyping, or using FISH for the BCR-ABL fusion.

Treatment and prognosis: Targeted therapy with tyrosine kinase inhibitors (TKIs) against BCR-ABL—such as imatinib, dasatinib, nilotinib, bosutinib, and ponatinib—has transformed management, especially in CML. Imatinib is commonly used first-line for CML, with newer TKIs employed for resistance or intolerance; ponatinib addresses specific mutations like T315I. Allogeneic stem cell transplantation remains an option for advanced disease after TKI failure. TKIs have markedly improved survival, though resistance can occur via ABL kinase domain mutations or other mechanisms.