Mechanistic and translational studies of CBF leukemia

National Human Genome Research Institute

Investigators

Linked publications & trials

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease with diverse gene mutations and chromosomal abnormalities. Core binding factor (CBF) leukemias, those with translocations or inversions that affect transcription factor genes RUNX1 or CBFB, account for approximately 24% of adult acute myeloid leukemia (AML) and 25% of pediatric acute lymphocytic leukemia. The encoded proteins, RUNX1 and CBFbeta, form a heterodimer to regulate gene expression, and they are both required for hematopoiesis in vertebrate animals such as zebrafish and mice. Extensive clinical studies have demonstrated that CBFB-MYH11 and RUNX1-ETO, the two common fusion genes in CBF leukemia, are the best biomarkers for diagnosis, prognosis, and residual disease monitoring of CBF leukemia patients. Over the years we have used mouse models and a variety of research tools to characterize the CBFB-MYH11 fusion gene, determine the effect of the encoded protein, CBFbeta-SMMHC, on normal hematopoiesis, and understand the leukemia development process associated with the fusion gene. We have generated both conventional and conditional knock-in mouse models to study CBFB-MYH11. Using these models we showed that CBFB-MYH11 is necessary but not sufficient for leukemia development, and we were able to identify cooperating genetic events in the mouse models. We have generated knock-in mouse models expressing truncated CBFB-MYH11 to determine the importance of functional domains of CBFbeta-SMMHC. Overall our lab has been recognized in the field as a major contributor to the understanding of CBFB-MYH11 leukemia. We recently showed that RUNX1 is indispensable for Cbfb-MYH11induced leukemogenesis in a mouse model. We found that RUNX1 interacted with CBF-SMMHC, the fusion protein encoded by CBFB-MYH11, to directly regulate critical genes for leukemogenesis (Zhen et al., Blood, 2020). Our more recent data suggest that the leukemogenic capability of CBFbeta-SMMHC correlates with its ability to enhance binding between RUNX1 and its target DNA and to form multimerized filaments. Moreover, we used single cell RNA-sequencing (scRNA-seq) to assess gene expression changes during the disease progression from normal to pre-leukemic to overt leukemia in the conditional Cbfb-MYH11 knock-in mouse model. The study investigated dynamic shifts in cell types as disease progresses, and gene expression differences between normal and diseased cells. The study identified a novel cell population in the pre-leukemic state with expression of genes involved in immune activation. Overall, this study discovered hematopoietic cells first affected by the expression of CBFb-SMMHC and identified unique signature genes for the pre-leukemic cells that separate them from the normal hematopoietic cellular milieu.