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Hematopoietic Stem Cells Are Intrinsically Protected against MLL-ENL-Mediated Transformation.

Ugale, Amol LU ; Norddahl, Gudmundur LU ; Wahlestedt, Martin LU ; Säwén, Petter LU ; Jaako, Pekka LU ; Pronk, Kees-Jan LU ; Soneji, Shamit LU ; Cammenga, Jörg LU and Bryder, David LU (2014) In Cell Reports 9(4). p.1246-1255
Abstract
Studies of developmental pathways of hematopoietic stem cells (HSCs) have defined lineage relationships throughout the blood system. This is relevant to acute myeloid leukemia (AML), where aggressiveness and therapeutic responsiveness can be influenced by the initial stage of transformation. To address this, we generated a mouse model in which the mixed-lineage leukemia/eleven-nineteen-leukemia (MLL-ENL) transcription factor can be conditionally activated in any cell type. We show that AML can originate from multiple hematopoietic progenitor subsets with granulocytic and monocytic potential, and that the normal developmental position of leukemia-initiating cells influences leukemic development. However, disease failed to arise from HSCs.... (More)
Studies of developmental pathways of hematopoietic stem cells (HSCs) have defined lineage relationships throughout the blood system. This is relevant to acute myeloid leukemia (AML), where aggressiveness and therapeutic responsiveness can be influenced by the initial stage of transformation. To address this, we generated a mouse model in which the mixed-lineage leukemia/eleven-nineteen-leukemia (MLL-ENL) transcription factor can be conditionally activated in any cell type. We show that AML can originate from multiple hematopoietic progenitor subsets with granulocytic and monocytic potential, and that the normal developmental position of leukemia-initiating cells influences leukemic development. However, disease failed to arise from HSCs. Although it maintained or upregulated the expression of target genes associated with leukemic development, MLL-ENL dysregulated the proliferative and repopulating capacity of HSCs. Therefore, the permissiveness for development of AML may be associated with a narrower window of differentiation than was previously appreciated, and hijacking the self-renewal capacity of HSCs by a potent oncogene is insufficient for leukemic development. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cell Reports
volume
9
issue
4
pages
1246 - 1255
publisher
Cell Press
external identifiers
  • pmid:25456127
  • wos:000345529600009
  • scopus:84912066449
ISSN
2211-1247
DOI
10.1016/j.celrep.2014.10.036
language
English
LU publication?
yes
id
5e61697d-38b5-442f-a21f-a4537e787eb9 (old id 4913111)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25456127?dopt=Abstract
date added to LUP
2015-01-08 16:34:41
date last changed
2017-10-01 04:31:29
@article{5e61697d-38b5-442f-a21f-a4537e787eb9,
  abstract     = {Studies of developmental pathways of hematopoietic stem cells (HSCs) have defined lineage relationships throughout the blood system. This is relevant to acute myeloid leukemia (AML), where aggressiveness and therapeutic responsiveness can be influenced by the initial stage of transformation. To address this, we generated a mouse model in which the mixed-lineage leukemia/eleven-nineteen-leukemia (MLL-ENL) transcription factor can be conditionally activated in any cell type. We show that AML can originate from multiple hematopoietic progenitor subsets with granulocytic and monocytic potential, and that the normal developmental position of leukemia-initiating cells influences leukemic development. However, disease failed to arise from HSCs. Although it maintained or upregulated the expression of target genes associated with leukemic development, MLL-ENL dysregulated the proliferative and repopulating capacity of HSCs. Therefore, the permissiveness for development of AML may be associated with a narrower window of differentiation than was previously appreciated, and hijacking the self-renewal capacity of HSCs by a potent oncogene is insufficient for leukemic development.},
  author       = {Ugale, Amol and Norddahl, Gudmundur and Wahlestedt, Martin and Säwén, Petter and Jaako, Pekka and Pronk, Kees-Jan and Soneji, Shamit and Cammenga, Jörg and Bryder, David},
  issn         = {2211-1247},
  language     = {eng},
  number       = {4},
  pages        = {1246--1255},
  publisher    = {Cell Press},
  series       = {Cell Reports},
  title        = {Hematopoietic Stem Cells Are Intrinsically Protected against MLL-ENL-Mediated Transformation.},
  url          = {http://dx.doi.org/10.1016/j.celrep.2014.10.036},
  volume       = {9},
  year         = {2014},
}