FACT Complex - A gatekeeper of differentiation in AML

Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with a dismal 5-year survival rate of ~32%. Given that the treatment of AML remains an unmet clinical need, it is critical to identify novel, therapeutic targets in AML. Differentiation blockade is the key problem in AML. Hallmarks of AML include myeloid progenitors proliferating constantly and failing to terminally differentiate into their mature, functional counterparts such as macrophages. Presently, there are only a few differentiation therapies for AML traversing the regulatory drug development pipeline. Available differentiation therapies are limited to specific subtypes of AML, for example, All-Trans Retinoic Acid (ATRA) for Promyelocytic Leukemia (PML) and Enasidenib for IDH2-mutated AML.To identify genes encoding druggable proteins essential in maintaining the undifferentiated state of AML, we designed a creative CRISPR screen. The screen revealed that FACT (FAcilitates Chromatin Transcription) complex is required for AML to maintain this undifferentiated state. The FACT complex is a key histone chaperone that stabilizes nucleosomes during transcription, DNA replication, and DNA repair. The FACT complex is overexpressed in AML patient samples, and its expression is significantly associated with poor patient prognosis. Little is known about its function in AML. In the present study, our goal is to explore the mechanistic role of FACT complex in AML differentiation. We also intend to exploit the dependency of the FACT complex in AML to develop therapeutic approaches to target AML.