Downregulation of Morrbid in Tet2-Deficient Preleukemic Cells Overcomes Resistance to Inflammatory Stress and Mitigates Clonal Hematopoiesis

Myeloid malignancies including AML, CMML, MPN and MDS are considered clonal blood disorders. Hematopoietic stem and progenitor cells (HSPCs) with mutation(s) in AML-related genes such as TET2 or DNMT3A represent what are commonly defined as preleukemic HSPCs. The selection and expansion of preleukemic-HSPC clones precedes the development of AML. Additionally, preleukemic-HSPCs can transform through serial acquisition of additional somatic mutations over time and contribute to the development of full-blown AML. What is unclear is the nature of environmental signals that might contribute to the “switch” from a preleukemic state to a leukemic state in these cells. In this context, inflammation has been hypothesized to play an essential role, but precisely how inflammatory signals influence the growth, survival, differentiation and the overall engraftment potential of preleukemic-HSPCs is yet to be determined. Mouse models carrying loss of function alleles in Tet2 or Dnmt3a manifest an expanded HSPC pool, including a hematopoietic stem cell (HSC)-enriched fraction defined by cell surface markers Lineage-/Sca-1+/c-Kit+ (LSK). Some of these genetically modified mice go on to develop CMML or MPN with modest penetration when aged. Majority of pre-leukemic mutations on their own are insufficient to cause AML in mice, suggesting that a single mutation among the above-described mutations define a pre-leukemic state and perhaps additional cooperating mutations are necessary to provide a more effective selection advantage for preleukemic-HSPC leading to the development of full-blown leukemia. Inflammation has been linked to tumor induction and transformation in solid tissues. Inflammation caused by environmental exposure, infection, autoimmunity, or ageing may result in mutations and genomic instability in somatic cells as well as in reprogramming of the tumor microenvironment (i.e. through regulating angiogenesis and expression of cytokines and chemokines). Considering that both innate and adaptive immune cells are generated from HSPCs and are involved in regulating local as well as whole-body inflammatory processes, the relationship between inflammation and hematopoietic malignancies is likely to be complex. While the influence of inflammatory stress on normal HSPCs has recently gained significant attention, little is known about how preleukemic HSPCs respond to inflammation. Because HSPCs reside in the bone marrow and are surrounded by mature immune cells, the infla