(MRC DTP) Functional and molecular alterations of human bone marrow mesenchymal stem cells in Chronic Myelomonocytic Leukaemia

Chronic myelomonocytic leukaemia (CMML) is a clonal stem cell neoplasm defined by abnormal monocytosis and dysplasia involving one or more myeloid blood cell lineages. Allogeneic haematopoietic stem cell transplantation is the only curative option for CMML, although advanced age and lack of suitable donors preclude many patients being considered for this therapy. There are few other treatment options for CMML patients and these are limited in significant part due to the poor understanding of the underlying mechanisms that drive disease progression. The mutational landscape in CMML has been well characterised; however how specific mutations lead to CMML and importantly whether cell extrinsic factors play any role in CMML progression have been not studied. The bone marrow niche plays a critical role in maintaining haematopoietic stem cell maintenance and differentiation towards myeloid and lymphoid lineages. Recent evidence indicates that the bone marrow niche is altered in certain types of leukaemias and these alterations promote leukemia cell survival whilst inhibiting normal haematopoiesis. Taking into account that CMML generally affects older adults and that the aged microenvironment is less capable of supporting normal haematopoiesis, I hypothesize that a defective niche in CMML could play a critical and potentially targetable role in disease initiation and progression. To test the overarching hypotheses, specific aims of the project are to 1) investigate alterations associated with CMML bone marrow niche 2) study the impact of CMML cells on the normal bone marrow niche. The prospective student will investigate whether bone marrow niche cells especially mesenchymal stem cells, which are major components of niche, in CMML patients are functionally and molecularly altered and if so what are the molecular mechanisms leading to these alterations. The student will also aim to understand the bidirectional cross talk between patient CMML cells and their niche using ex vivo cultures and in vivo transplantation studies combined with transcriptomic and epigenomic approaches. Investigating the role of the niche in CMML is important because understanding the niche-mediated regulation of haematopoietic cell dysfunction in CMML may highlight novel and much needed alternative/adjunctive therapeutic strategies in CMML, through targeted manipulation of the microenvironment to both impair CMML cell survival and restore normal background haematopoiesis.

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