Generation of leukaemia cell hierarchies by MLL fusion oncogenes


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Tim Somervaille
Paterson Institute for Cancer Research, Manchester, United Kingdom

Abstract

MLL fusion oncogenes are pathogenically associated with 5–10% of human acute leukaemias. Through multiple interactions with chromatin regulatory factors, they convert a normal haematopoietic hierarchy into a leukaemia cell hierarchy sustained at its apex by a population of inappropriately self-renewing cells termed leukaemia stem cells (LSCs). Human and murine studies have demonstrated that initiation of the aberrant leukaemia cell hierarchy is associated with and dependent upon an abnormal epigenetic state at Hoxa and Meis1 loci and concomitant high level Hoxa and Meis1 expression. Murine leukaemia initiation models have demonstrated that the self-renewing cells are most similar to normal myeloblasts by immunophenotype and transcriptional profile, rather than normal haematopoietic stem cells (HSCs). In contrast, differentiation-mediated exit of LSCs from the self-renewing compartment of the leukaemia clone depends on the prevailing levels of the transcription factor Myb, which functions as part of an LSC maintenance program influenced, but not directly controlled, by Hoxa and Meis1. Critical biological and molecular differences between self-renewing progenitor-like LSCs and normal HSCs could potentially be targeted by novel therapeutic strategies. The challenge now is to identify which genes and cellular pathways are absolutely required for self-renewal in the context of a leukaemia stem cell but are of lesser importance to the function of normal HSCs.