Hematopoietic stem cells in your bone marrow produce about 1 trillion blood cells per day, and we rely on this massive cellular output to continue for eight decades or longer. When this process goes awry, bone marrow failure or leukemia can develop. In the Voit lab, we are interested in elucidating and mechanistically characterizing the factors that control stem cell maintenance and hematopoietic cell fate decisions. In doing so, we seek a deeper understanding of the transcriptional and translational regulation of hematopoiesis which will lead to better, targeted therapies for acute myeloid leukemia and inform the next generation of gene therapy for inherited bone marrow failure syndromes.
Regulated GATA1 expression as a gene therapy cure for DBA
Despite the genetic heterogeneity of DBA, erythroid progenitors in all DBA patients undergo maturation arrest due to ribosomal dysfunction, which converges on impaired translation of the erythroid master regulator GATA1. This observation provides a potential avenue for a unified gene therapy approach that would be applicable to all DBA patients, irrespective of the underlying genotype. Previous work revealed a rescue of erythroid differentiation arrest in DBA patient samples by constitutive overexpression of GATA1, but unregulated expression of GATA1 in hematopoietic stem cells (HSC) leads to forced erythroid differentiation at the expense of HSC maintenance. To overcome this limitation, we dissected the endogenous regulatory elements governing GATA1 expression in erythroid cells to engineer the human GATA1 enhancer (hG1E) element which leads to developmentally faithful, erythroid-lineage restricted expression of transgenes. We synthesized a clinical-grade lentiviral hG1E-GATA1 vector that augments erythroid output in primary DBA patient samples of varied genotypes without impacting HSC function (Voit et al, manuscript submitted, 2024). We are currently pursuing regulatory approval to initiate the first-in-human universal gene therapy trial for DBA.
Mechanisms of erythroid maturation arrest in Diamond-Blackfan anemia
Diamond-Blackfan anemia (DBA) is a bone marrow failure syndrome that is characterized by impaired red blood cell production leading to severe anemia. The only available treatment options are chronic red blood cell transfusions, corticosteroids, or hematopoietic stem cell transplantation (HSCT). More effective, safer, and permanent cures for DBA are lacking, but few drugs are in active development. To develop novel therapies for DBA, a deeper mechanistic insight into physiological erythroid differentiation is essential. More than 30 mutations are known cause DBA or DBA-like syndrome through impaired ribosome function, but almost a quarter of DBA patients have no identifiable genetic cause. We have established unbiased, high-throughput systems to uncover factors that impair erythroid differentiation, and are using them to identify novel regulators of this process. Using primary patient samples and whole genome sequencing of genetically undefined DBA patients, we aim to elucidate novel DBA genes that will deepen our understanding of physiologic erythroid differentiation.
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 2023). 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, 2024). In doing so, we aim to elucidate vulnerabilities in the MECOM network that can be targeted by the next generation of AML therapeutics.
