COLUMBIA UNIVERSITY • DEPARTMENT OF
Physiology and Cellular Biophysics

CURRENT RESEARCH

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My laboratory studies the biology of hematopoietic stem cells (HSCs) and how acquisition of oncogenic mutations transforms HSCs into myeloid malignancies, including myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We leverage patient-derived induced pluripotent stem cells (iPSCs) and gene editing of primary human HSCs to study how mutation cooperation drives malignant transformation. Our long-term goal is to identify fundamental mechanisms of disease and to develop targeted therapies to eradicate malignant stem cells.

Human HSCs reside in the bone marrow and sustain life-long hematopoiesis. Over decades, HSCs can acquire oncogenic mutations that confer competitive advantage to HSCs leading to clonal expansions. Over time these premalignant states can progress to leukemias due to complex interplay between mutations and environmental factors. We showed that iPSC reprogramming can capture the HSC genetic clones and inform the order and contribution of somatic mutations in clonal evolution (Hsu et al. 2019). Using the iPSC and primary human model systems, our research seeks to uncover fundamental mechanisms by which genetic driver mutations promote clonal expansion and progression from premalignant to neoplastic states.

Two major directions in the lab are focused on: SF3B1 splicing factor mutations and chromosome 5q deletions. Spliceosome mutations are the most common drivers in MDS. We are exploring how aberrant gene splicing due to mutant SF3B1 dysregulates hematopoiesis leading to MDS. We recently identified mis-splicing of mitochondrial genes TMEM14C and ABCB7 as the cause of ring sideroblast formation in MDS (Clough et al. 2022) and uncovered inhibition of CHK1 as a selective therapeutic vulnerability of SF3B1 mutated HSCs (Sarchi et al. 2024). Chromosome 5q is the most commonly deleted region in myeloid neoplasms, including high-risk MDS/AML with complex karyotype. We recently identified lamin B1/LMNB1 encoded on chr. 5q as the critical regulator of HSC function and nuclear morphology via higher-order genome organization (Reilly et al. 2022). We are interested in understanding how genome organization shapes normal and neoplastic hematopoiesis.

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sd3923@cumc.columbia.edu