Targeting binding partners of the CBFβ-SMMHC fusion protein for the treatment of inversion 16 acute myeloid leukemia

Abstract

Inversion of chromosome 16 (inv(16)) generates the CBFβ-SMMHC fusion protein and is found in nearly all patients with acute myeloid leukemia subtype M4 with Eosinophilia (M4Eo). Expression of CBFβ-SMMHC is causative for leukemia development, but the molecular mechanisms underlying its activity are unclear. Recently, there have been important advances in defining the role of CBFβ-SMMHC and its binding partners, the transcription factor RUNX1 and the histone deacetylase HDAC8. Importantly, initial trials demonstrate that small molecules targeting these binding partners are effective against CBFβ-SMMHC induced leukemia. This review will discuss recent advances in defining the mechanism of CBFβ-SMMHC activity, as well as efforts to develop new therapies for inv(16) AML.

Keywords: AML; CBFβ; CBFβ-SMMHC; RUNX1; inv(16).

Figure 1. Schematic representation of the CBFβ-SMMHC fusion protein

Diagram representing the indicated domains of the fusion protein, and the associated amino acid (aa) numbers. HABD: High Affinity Binding Domain. ACD: Assembly Competence Domain.

Figure 2. Small molecules targeting CBFβ-SMMHC

Table listing current small molecule inhibitors targeting CBFβ-SMMHC, and other disease models each drug has been tested in. AML: Acute Myeloid Leukemia. ALL: Acute Lymphoid Leukemia. CNS: Central Nervous System.

Figure 3. Proposed mechanism of CBFβ-SMMHC inhibitors

Schematic representation of proposed CBFβ-SMMHC activities A. in the absence of inhibitors, or in the presence of B. Ro5-3335, C. AI-10-49, or D. 22d. Proteins are represented by the colored shapes labeled in (A). Ac: Acetylation group.