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Mll-AF4 Confers Enhanced Self-Renewal and Lymphoid Potential during a Restricted Window in Development.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Barrett, Neil A 
Malouf, Camille 
Kapeni, Chrysa 
Bacon, Wendi A 
Giotopoulos, George  ORCID logo  https://orcid.org/0000-0003-1390-6592

Abstract

MLL-AF4+ infant B cell acute lymphoblastic leukemia is characterized by an early onset and dismal survival. It initiates before birth, and very little is known about the early stages of the disease's development. Using a conditional Mll-AF4-expressing mouse model in which fusion expression is targeted to the earliest definitive hematopoietic cells generated in the mouse embryo, we demonstrate that Mll-AF4 imparts enhanced B lymphoid potential and increases repopulation and self-renewal capacity during a putative pre-leukemic state. This occurs between embryonic days 12 and 14 and manifests itself most strongly in the lymphoid-primed multipotent progenitor population, thus pointing to a window of opportunity and a potential cell of origin. However, this state alone is insufficient to generate disease, with the mice succumbing to B cell lymphomas only after a long latency. Future analysis of the molecular details of this pre-leukemic state will shed light on additional events required for progression to acute leukemia.

Description

Keywords

Animals, Cell Self Renewal, Leukemia, Lymphocytes, Lymphoma, B-Cell, Mice, Mice, Transgenic, Myeloid-Lymphoid Leukemia Protein, Oncogene Proteins, Fusion, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma

Journal Title

Cell Rep

Conference Name

Journal ISSN

2211-1247
2211-1247

Volume Title

Publisher

Elsevier BV
Sponsorship
Medical Research Council (MR/M010392/1)
Medical Research Council (MC_PC_12009)
European Research Council (647685)
Wellcome Trust (093026/Z/10/Z)
Wellcome Trust (097454/Z/11/A)
Wellcome Trust (100140/Z/12/Z)
Worldwide Cancer Research (None)
Core facilities at the Cambridge Institute for Medical Research are supported by Strategic Award WT100140 and equipment grant 093026; core facilities at the Edinburgh MRC Centre for Regenerative Medicine are supported by centre grant MR/K017047/1. This work was funded by a Bloodwise Bennett Senior Fellowship (10015 to K.O.), a Wellcome Trust Clinical PhD Studentship (097454/z/11/z to N.A.B.) the Gabrielle’s Angel Foundation for Cancer Research (to K.O.), and the Kay Kendall Leukaemia Fund (to K.O.).