Doulatov Lab

Change-of-function mutations in the spliceosomal gene SF3B1 are recurrent and frequent somatic lesions that alter RNA splicing in premalignant clonal hematopoiesis and ~30% of patients with MDS. We are studying how aberrantly spliced gene isoforms generated by mutant SF3B1 dysregulate hematopoiesis and erythropoiesis 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. Blood 2022; cover image). We also uncovered inhibition of CHK1 as a selective therapeutic vulnerability of SF3B1 mutated HSCs (Sarchi et al. Blood Cancer Discovery 2024).

An abnormal chromosome complement, or aneuploidy, is a hallmark of high-risk myeloid malignancies with TP53 mutations and complex karyotype (AML-CK). We are studying how aneuploidy first arises in HSCs and how it evolves to AML-CK using a novel iPSC model system in which normal HSCs evolve to complex aneuploidies. Current work is focused on the role and genetics of chromosome 5q deletions in AML-CK and therapeutic targeting of aneuploidy.

The spatial organization of the genome inside the nucleus is essential for hematopoietic fate determination, and is often perturbed in leukemic transformation. We uncovered lamin B1 as the key regulator of HSC function and nuclear morphology (Reilly et al. Cell Stem Cell 2022). We are studying genome organization and its regulation by lamins in normal and neoplastic hematopoiesis.

The image depicts two chefs cooking a bowl of “noodle chromatin”, one with LMNB1 and one deprived of it. With LMNB1, chromatin is organized and HSC fate is normal. Without LMNB1, on the right, chromatin is disorganized leading to altered HSC fate, nuclear anomaly, and disrupted DNA repair shown by the broken bowls at the end of the conveyor belt. Illustration developed for Reilly et al. 2022 by Emma Vidal.