Hematopoietic stem cell transcription networks hijacked in leukemia

Dysregulated gene expression in hematopoietic stem cells (HSCs) perturbs the balance of self-renewal and differentiation signals and underlies oncogenic transformation in a subset of acute myeloid leukemia (AML). A deeper mechanistic understanding of gene regulation in hematopoiesis and dysregulation in leukemia is essential to develop more effective, targeted treatments for AML and to prevent cancer development following gene therapy and forms the scientific basis of my research program. Despite recent advances in the treatment of AML, many patients experience treatment failure or disease relapse. Increasing evidence suggests that the acquisition of HSC gene expression programs in AML confers a poor prognosis. Recently, we elucidated a fundamental gene regulatory network essential for HSC maintenance that is hijacked in high-risk forms of AML – while studying a neonatal bone marrow failure syndrome caused by haploinsufficiency of the transcription factor MECOM (Voit et al, Nature Immunology 2022). However, there remains a limited understanding of how this gene network regulates cell state in normal and malignant hematopoiesis and which downstream effectors of MECOM are crucial for HSC and leukemia stem cell survival. Current projects in the lab seek to explore intrinsic and potentially targetable vulnerabilities in the MECOM network, including in MECOM. We are using CRISPR-based perturbations of MECOM and essential co-regulators, coupled with sensitive functional, genomic, transcriptomic, and epigenomic profiling to provide mechanistic insights into the profound loss of HSCs in MECOM deficiency syndrome, a neonatal bone marrow failure syndrome (Voit and Sankaran, Clinical Immunology, 2023). In doing so, we aim to elucidate vulnerabilities in the MECOM network that can be targeted by the next generation of AML therapeutics.

Selected Publications

MECOM deficiency: from bone marrow failure to impaired B-cell development
Voit RA., Sankaran VG. (2023) Journal of Clinical Immunology 43(6):1052-1066. [DOI]

A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia
Voit, RA., Tao, L., Yu, F., Cato, L. D., Cohen, B., Fleming, T., Antoszewski, M., Liao, X., Fiorini, C., Nandakumar, S., Wahlster, L., Teichert, K., Regev, A., & Sankaran, V. (2022) Nature Immunology 24, 69–83. [DOI]