Functional Alterations of Lin−CD34+CD38+ Progenitors in Chronic Myelomonocytic Leukaemia and on Progression to Acute Leukaemia.

Abstract

Chronic myelomonocytic leukaemia (CMML) is a clonal bone marrow stem cell disorder based on the presence of trilineage involvement, the association of myelodysplastic and myeloproliferative features and its ability to transform into acute myeloid leukaemia. The objectives of our study are to identify the cell population and its functional characteristics involved in evolution from CMML phase to acute myeloid leukaemia. We analysed Lin−CD34+ stem/progenitor population and performed cell proliferation, apoptotic assays, self-renewal ability and differentiation potential studies in purified populations of Lin−CD34+CD38− stem cells and Lin−CD34+CD38+ committed progenitors from peripheral blood of 16 patients with CMML and in six of the 16 after transformation to acute myeloid leukaemia (AML-t). We observed an expansion of the stem cell/progenitor pool (Lin−CD34+ cells) in AML-t comprising mainly of Lin−CD34+CD38+ committed progenitors within Lin−CD34+ cells. The Lin−CD34+CD38+ committed progenitors displayed highly proliferative activity in CMML and in AML-t; and additionally acquired resistance to apotosis and myeloid colony self-renewing ability in AML-t. Impairment of dendritic cell (DC) differentiation was observed with complete block in AML-t. Our findings suggest Lin−CD34+CD38+ committed progenitors instead of Lin−CD34+CD38− stem cells could be the target(s) of secondary genetic lesions underpinning progression from CMML to AML. These results have implications for the further study of the biology of leukaemic transformation and the design of new strategies for the effective treatment of CMML.