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Dysregulation of haematopoietic stem cell regulatory programs in acute myeloid leukaemia.

Published version
Peer-reviewed

Type

Article

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Authors

Basilico, Silvia 
Göttgens, Berthold 

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.

Description

Keywords

ALL, AML, HSPC, MLL gene, Animals, Cell Differentiation, Cell Transformation, Neoplastic, Gene Expression Regulation, Leukemic, Hematopoietic Stem Cells, Histone-Lysine N-Methyltransferase, Humans, Leukemia, Myeloid, Acute, Mutation, Myeloid-Lymphoid Leukemia Protein, Oncogene Fusion

Journal Title

J Mol Med (Berl)

Conference Name

Journal ISSN

0946-2716
1432-1440

Volume Title

95

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research UK (CRUK-A19405)
Medical Research Council (MC_PC_12009)
Medical Research Council (MR/M008975/1)
Wellcome Trust (097922/Z/11/Z)
Wellcome Trust (097922/Z/11/B)
Cancer Research UK (21762)