Dissecting intrinsic and extrinsic mechanisms in the clonal expansion of the hematopoietic stem cells in del(5q) MDS

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Myelodysplastic syndrome (MDS) is characterized by dysplastic hematopoiesis, peripheral cytopenias and frequent transformation to acute myeloid leukemia (AML). Deletions of chromosome 5q are the most common cytogenetic abnormality in MDS and are associated with a consistent clinical phenotype, termed the 5q- syndrome. 5q- hematopoietic stem cells (HSCs) gain an advantage in the bone marrow and outcompete normal blood formation. One critical and yet unsolved question is how this heterozygous genetic lesion contributes to clonal advantage, clonal persistence and malignant transformation.In my preliminary work in the host group (R. Schneider, Erasmus MC, Rotterdam, NL), I have systematically compared candidate genes located in the common deleted region on chromosome 5, that supposedly contribute to clonal advantage of HSC when in haploinsufficient state (50% downregulation of gene expression). I identified two haploinsufficient genes that lead to oligoclonal expansion of the HSC and outcompete normal hematopoiesis – Csnk1a1 and Egr1. The main goal of this proposal is to determine how HSCs with Csnk1a1 and Egr1 haploinsufficiency gain an advantage in the bone marrow and how the bone marrow microenvironment is altered and supports this advantage.In aim 1, I will investigate the cell intrinsic mechanism of Csnk1a1 and Egr1 haploinsufficiency leading to clonal expansion, individually and in combination, using novel inducible genetic mouse models and bone marrow transplantation. In aim 2, I will determine how commonly found TP53 mutations in del(5q) MDS collaborate with these candidate genes in malignant transformation of the del(5q) clone using in vivo CRISPR/Cas9 genome editing. In aim 3, I will dissect how the bone marrow microenvironment is altered by the del(5q) MDS clone and how this alteration potentially contributes to the disease phenotype and progression, using novel hematopoietic and mesenchymal cell lines, that the host group has generated, in combination with single-cell transcriptomics in primary patient samples. My proposed studies will continue to elucidate the mechanisms underlying the MDS phenotype for this common and important genetic lesion and provide further insight into the biology of large heterozygous deletions in cancer more broadly.