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FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors

Mead, Adam J.; Kharazi, Shabnam LU ; Atkinson, Deborah; Macaulay, Iain; Pecquet, Christian; Loughran, Stephen; Lutteropp, Michael; Woll, Petter; Chowdhury, Onima and Luc, Sidinh, et al. (2013) In Cell Reports 3(6). p.1766-1776
Abstract
Whether signals mediated via growth factor receptors (GFRs) might influence lineage fate in multipotent progenitors (MPPs) is unclear. We explored this issue in a mouse knockin model of gain-of-function Flt3-ITD mutation because FLT3-ITDs are paradoxically restricted to acute myeloid leukemia even though Flt3 primarily promotes lymphoid development during normal hematopoiesis. When expressed in MPPs, Flt3-ITD collaborated with Runx1 mutation to induce high-penetrance aggressive leukemias that were exclusively of the myeloid phenotype. Flt3-ITDs preferentially expanded MPPs with reduced lymphoid and increased myeloid transcriptional priming while compromising early B and T lymphopoiesis. Flt3-ITD-induced myeloid lineage bias involved... (More)
Whether signals mediated via growth factor receptors (GFRs) might influence lineage fate in multipotent progenitors (MPPs) is unclear. We explored this issue in a mouse knockin model of gain-of-function Flt3-ITD mutation because FLT3-ITDs are paradoxically restricted to acute myeloid leukemia even though Flt3 primarily promotes lymphoid development during normal hematopoiesis. When expressed in MPPs, Flt3-ITD collaborated with Runx1 mutation to induce high-penetrance aggressive leukemias that were exclusively of the myeloid phenotype. Flt3-ITDs preferentially expanded MPPs with reduced lymphoid and increased myeloid transcriptional priming while compromising early B and T lymphopoiesis. Flt3-ITD-induced myeloid lineage bias involved upregulation of the transcription factor Pu.1, which is a direct target gene of Stat3, an aberrantly activated target of Flt3-ITDs, further establishing how lineage bias can be inflicted on MPPs through aberrant GFR signaling. Collectively, these findings provide new insights into how oncogenic mutations might subvert the normal process of lineage commitment and dictate the phenotype of resulting malignancies. (Less)
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published
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Cell Reports
volume
3
issue
6
pages
1766 - 1776
publisher
Cell Press
external identifiers
  • wos:000321901200003
  • scopus:84879797933
ISSN
2211-1247
DOI
10.1016/j.celrep.2013.04.031
language
English
LU publication?
yes
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d0226c4a-366d-41e3-83cd-3ef3a199bdb7 (old id 3975179)
date added to LUP
2013-09-02 07:36:49
date last changed
2019-04-23 02:20:46
@article{d0226c4a-366d-41e3-83cd-3ef3a199bdb7,
  abstract     = {Whether signals mediated via growth factor receptors (GFRs) might influence lineage fate in multipotent progenitors (MPPs) is unclear. We explored this issue in a mouse knockin model of gain-of-function Flt3-ITD mutation because FLT3-ITDs are paradoxically restricted to acute myeloid leukemia even though Flt3 primarily promotes lymphoid development during normal hematopoiesis. When expressed in MPPs, Flt3-ITD collaborated with Runx1 mutation to induce high-penetrance aggressive leukemias that were exclusively of the myeloid phenotype. Flt3-ITDs preferentially expanded MPPs with reduced lymphoid and increased myeloid transcriptional priming while compromising early B and T lymphopoiesis. Flt3-ITD-induced myeloid lineage bias involved upregulation of the transcription factor Pu.1, which is a direct target gene of Stat3, an aberrantly activated target of Flt3-ITDs, further establishing how lineage bias can be inflicted on MPPs through aberrant GFR signaling. Collectively, these findings provide new insights into how oncogenic mutations might subvert the normal process of lineage commitment and dictate the phenotype of resulting malignancies.},
  author       = {Mead, Adam J. and Kharazi, Shabnam and Atkinson, Deborah and Macaulay, Iain and Pecquet, Christian and Loughran, Stephen and Lutteropp, Michael and Woll, Petter and Chowdhury, Onima and Luc, Sidinh and Buza-Vidas, Natalija and Ferry, Helen and Clark, Sally-Ann and Goardon, Nicolas and Vyas, Paresh and Constantinescu, Stefan N. and Sitnicka Quinn, Ewa and Nerlov, Claus and Jacobsen, Sten Eirik W.},
  issn         = {2211-1247},
  language     = {eng},
  number       = {6},
  pages        = {1766--1776},
  publisher    = {Cell Press},
  series       = {Cell Reports},
  title        = {FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors},
  url          = {http://dx.doi.org/10.1016/j.celrep.2013.04.031},
  volume       = {3},
  year         = {2013},
}