CBFB – Acute Myeloid Leukemia

CBFB encodes the beta‐subunit of the core-binding transcription factor complex, which heterodimerizes with RUNX1 to regulate hematopoietic differentiation. Somatic rearrangements of CBFB with MYH11 via inv(16)(p13q22) or t(16;16)(p13;q22) define the core-binding factor (CBF) acute myeloid leukemia (AML) subtype, classified under MONDO:0018874 Gene Symbol – Acute Myeloid Leukemia.

Detection of CBFB/MYH11 fusions in de novo AML has been demonstrated in a cohort of 224 Japanese adult patients, with 17 individuals (7.6%) harboring the fusion transcript by RT-PCR and FISH, including nine with cryptic rearrangements not evident by conventional cytogenetics (PMID:17052753). Fluorescence in situ hybridization applied prospectively to 10 AML-M4Eo patients identified inv(16)/t(16;16) in all cases, one of which was undetected by karyotype, and RT-PCR confirmed CBFB/MYH11 transcripts in each (PMID:10800163).

The fusion breakpoint typically joins CBFB exon 5 at c.495 to MYH11 exon 12 at c.1201, yielding chimeric CBFB–MYH11 proteins that dominantly inhibit normal CBF activity. Although exact HGVS coding changes for CBFB are not systematically reported in these studies, the recurrent nature of the inv(16)/t(16;16) event underscores a consistent variant spectrum driving leukemogenesis across populations.

CBFB–MYH11 AML cases often present with myelomonocytic differentiation and bone marrow eosinophilia (HP:0001880), though atypical morphologies lacking eosinophilia have been described. Co-occurring mutations in FLT3, KRAS/NRAS, KIT, and other signaling genes further modulate prognosis and therapy response in this otherwise favorable-risk subgroup.

Functional assays have elucidated the mechanism of pathogenesis: the CBFB–SMMMHC oncoprotein multimerizes via its assembly competence domain, sequesters RUNX1, and disrupts RUNX1/p300 phosphorylation by HIPK2, leading to transcriptional repression of differentiation programs (PMID:16767164). Mouse models demonstrate that haploinsufficiency or dominant-negative disruption of CBFB phenocopy the differentiation block and predispose to leukemic transformation.

No studies to date refute the pathogenic role of CBFB rearrangements in CBF-AML; the high concordance of cytogenetic, molecular, and functional data across independent cohorts supports a definitive association.

Integration of genetic and experimental findings confirms that CBFB–MYH11 fusions drive a distinct leukemic entity with characteristic clinical and morphologic features. Molecular screening for CBFB/MYH11 by RT-PCR or FISH is essential for accurate risk stratification and therapeutic decision making in AML.

Key Take-home: Somatic CBFB–MYH11 rearrangements via inv(16)/t(16;16) define a core-binding factor AML subtype with favorable prognosis that requires molecular testing for optimal clinical management.

References

• Leukemia Research • 2007 • Detection of the CBFB/MYH11 fusion gene in de novo acute myeloid leukemia (AML): a single-institution study of 224 Japanese AML patients. PMID:17052753
• Haematologica • 2000 • Detection of inv(16) and t(16;16) by fluorescence in situ hybridization in acute myeloid leukemia M4Eo. PMID:10800163
• Oncogene • 2006 • Identification of a region on the outer surface of the CBFbeta-SMMHC myeloid oncoprotein assembly competence domain critical for multimerization. PMID:16767164

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