Rearrangements involving genes encoding components of the core binding factor (CBF) are present in approximately 15% of AML cases (generally, in younger patients). CBF is a heterodimeric transcription factor that is composed of an alpha subunit (encoded by RUNX1) that binds to a consensus DNA sequence, and a beta subunit (encoded by CBFB) that increases the affinity of the complex for DNA. The t(8;21) is found in up to 10% of AML cases and creates an in-frame fusion of RUNX family transcription factor 1 (RUNX1) with RUNX1 partner transcriptional co-repressor 1 (RUNX1T1) (encoding CBFA2T1, or ETO). This rearrangement is enriched in the FAB M2 subgroup and composes up to 40% of this patient subgroup. This fusion protein alters the CBF transcription factor complex, allowing it to oligomerize and interact with a nuclear corepressor complex that includes nuclear co-repressor 1 (NCOR1), histone deacetylas 1 (HDAC1), and SIN3 transcription regulator family member a (SIN3A)/HDAC, resulting in reduced RUNX1 target gene expression. The RUNX1-RUNX1T1 fusion protein functions as a dominant negative inhibitor of wild-type CBF and consequently impairs hematopoietic differentiation. The fusion protein also leads to activation of TP53 response genes, which may in part explain the relative chemosensitivity of t(8;21) AML. In addition to t(8;21), RUNX1 is involved in more than 50 other trans locations, including t(16;21)(q24;q22) with myeloid translocation gene on chromosome 16 (MGT16), and t(3;21)(q26;q22), with the MECOM (“MDS1 and EVI1 complex”) locus. RAS pathway mutations (affecting KIT, FLT3, N/KRAS, CBL) are present in more than half of t(8;21) cases and are associated with a higher risk of disease relapse. Frequent co-occurring mutations also include components of the cohesin complex (SMC1A, SMC3, RAD21), chromatin modifiers (ASXL1, ASXL2, EZH2), and epigenetic regulators (TET2, IDH1/2).
Chromosomal alterations involving CBFB include inv(16) and t(16;16)(p13;q22), which create an in-frame fusion between CBFB and MYH11, the gene encoding smooth muscle myosin heavy chain 11. AML with inv(16) or t(16;16) is often associated with the FAB M4eo phenotype. The CBFB-MYH11 gene product exerts a dominant negative effect on RUNX1 and can recruit nuclear corepressors to inhibit transcription of CBF gene targets. Mouse models with a CBF MYH11 knock-in mutation require additional mutations to progress to AML. Similar to t(8;21) AML, co-occurring RAS pathway mutations are common in patients with inv(16) AML, but mutations in chroma tin modifiers and the cohesin complex are underrepresented in inv(16) AML. Given the clear link between CBF rearrangements, as well as the PML-RARA translocation, and the development of AML, the presence of any of these is sufficient for a diagnosis of AML, regardless of the percentage of myeloblasts in the bone marrow or peripheral blood.
