Dysregulation of haematopoietic stem cell regulatory programs in acute myeloid leukaemia

Abstract

Haematopoietic stem cells (HSC) are situated at the apex of the haematopoietic differentiation hierarchy, ensuring the life-long supply of mature haematopoietic cells and forming a reservoir to replenish the haematopoietic system in case of emergency such as acute blood loss. To maintain a balanced production of all mature lineages and at the same time secure a stem cell reservoir, intricate regulatory programs have evolved to control multi-lineage differentiation and self-renewal in haematopoietic stem and progenitor cells (HSPCs). Leukaemogenic mutations commonly disrupt these regulatory programs causing a block in differentiation with simultaneous enhancement of proliferation. Here, we briefly summarize key aspects of HSPC regulatory programs, and then focus on their disruption by leukaemogenic fusion genes containing the mixed lineage leukaemia (MLL) gene. Using MLL as an example, we explore important questions of wider significance that are still under debate, including the importance of cell of origin, to what extent leukaemia oncogenes impose specific regulatory programs and the relevance of leukaemia stem cells for disease development and prognosis. Finally, we suggest that disruption of stem cell regulatory programs is likely to play an important role in many other pathologies including ageing-associated regenerative failure.

Keywords: ALL; AML; HSPC; MLL gene.

Fig. 1.

Perturbation of haematopoietic development by MLL rearrangements (MLL-r). MLL-r impair self-renewal and differentiation properties of HSCs and HSPCs. MLL driven leukaemic transformation has been mainly described in HSC, CMP, GMP and CLP [31, 33, 75, 76, 81, 86, 87, 92]. MPP and LMPP progenitors are also targets of MLL transformation as cellular permissiveness might be influenced by the specific strategy used to purify HSPCs [5, 91]. Biology and prognosis of AML and ALL bearing MLL translocations depend on multiple factors: cell of origin of leukaemic transformation, type of MLL-r, oncogene delivery methods, microenvironment and secondary mutations.