4.8 Article

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

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CELL REPORTS
卷 3, 期 6, 页码 1766-1776

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CELL PRESS
DOI: 10.1016/j.celrep.2013.04.031

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资金

  1. Leukaemia and Lymphoma Research Senior Bennett Fellowship
  2. Pasteur Institute of Iran
  3. Strategic Appointment and Programme grant from the Medical Research Council (UK)
  4. Hemato-Linne grant (Swedish Research Council Linnaeus)
  5. National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust
  6. Fondation contre le cancer, Salus Sanguinis, Action de Recherche Concertee and Interuniversity Attraction Poles Programs and Fonds de la Recherche Scientifique, Belgium
  7. Ludwig Institute for Cancer Research
  8. MRC [MC_UU_12009/5, G84/6443, MC_UU_12009/7, G0900892, MC_UU_12009/11, G0801073, MC_PC_12020, G1000729, MC_U137961146, G0501838] Funding Source: UKRI
  9. Medical Research Council [G1000801c, MC_PC_12020, G0900892, G84/6443, G1000729, MC_UU_12009/5, MC_UU_12009/7, MC_U137961146, MC_UU_12009/11, G0501838, G0801073] Funding Source: researchfish

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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.

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