The role of lamin B1 in normal and myelodysplastic hematopoiesis

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ABSTRACT Hematopoietic stem cells (HSCs) maintain life-long blood production and acquire somatic mutations leading to premalignant clonal expansion and myelodysplastic syndromes (MDS). Eukaryotic genomes are hierarchically organized at distinct spatial levels. However, it is largely unclear how this higher order three-dimensional (3D) genome organization orchestrates coordinate regulation of gene expression underlying developmental fate decisions. Nuclear lamins are structural proteins that establish genome architecture and play a prominent role in stem cells and disease. Lamin B1 is the most abundant nuclear lamin in hematopoietic cells, and its expression is broadly decreased in aging and due to recurrent 5q deletions in MDS. However, we lack a fundamental understanding of how lamin B1 regulates genome organization, how this 3D organization impacts HSC fate decisions, and whether 5q deletion of LMNB1 contributes to MDS pathogenesis and progression. Here, we propose to systematically answer these outstanding questions to gain a fundamental understanding of how lamin B1 contributes to normal and MDS hematopoiesis. Our team consists of a stem cell biologist with expertise in hematologic disease modeling (Doulatov), a molecular biologist with expertise in 3D genomes (Duan), computational biologist with expertise in 3D genomes (Noble), and a biochemist with expertise in chromatin regulation (Escobar). In preliminary studies, we examined the molecular and functional consequences of lamin B1 loss on human hematopoiesis. These experiments revealed that lamin B1 loss alters chromatin organization and nuclear morphology and promotes HSC and myeloid cell fates at the expense of lymphopoiesis. We propose to build on these preliminary studies as follows: Aim 1, Determine the role of lamin B1 and LBR in human HSC function and clonal dynamics in vivo; Aim 2, Define how lamin B1 regulates chromatin architecture and gene expression to control HSC fate; Aim 3, Determine whether 5q deletion of LMNB1 underlies impaired hematopoiesis in del5q MDS. The significance of these studies is that they will elucidate how lamin-dependent 3D genome regulates HSC fate. The health relevance is that the proposed work may identify lamin B1 as a tumor suppressor in del5q MDS. Since 5q deletion is often associated with high-risk MDS, these studies will help identify a major genetic driver and explore therapeutic vulnerabilities for this disorder.