title: FLT3-ITDs instruct a myeloid differentiation and transformation bias in lymphomyeloid multipotent progenitors.
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.
authors.affiliation: Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. adam.mead@imm.ox.ac.uk
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Mead
authors.forename: Shabnam
authors.initials: S
authors.lastname: Kharazi
authors.forename: Deborah
authors.initials: D
authors.lastname: Atkinson
authors.forename: Iain
authors.initials: I
authors.lastname: Macaulay
authors.forename: Christian
authors.initials: C
authors.lastname: Pecquet
authors.forename: Stephen
authors.initials: S
authors.lastname: Loughran
authors.forename: Michael
authors.initials: M
authors.lastname: Lutteropp
authors.forename: Petter
authors.initials: P
authors.lastname: Woll
authors.forename: Onima
authors.initials: O
authors.lastname: Chowdhury
authors.forename: Sidinh
authors.initials: S
authors.lastname: Luc
authors.forename: Natalija
authors.initials: N
authors.lastname: Buza-Vidas
authors.forename: Helen
authors.initials: H
authors.lastname: Ferry
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Clark
authors.forename: Nicolas
authors.initials: N
authors.lastname: Goardon
authors.forename: Paresh
authors.initials: P
authors.lastname: Vyas
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.forename: Ewa
authors.initials: E
authors.lastname: Sitnicka
authors.forename: Claus
authors.initials: C
authors.lastname: Nerlov
authors.forename: Sten Eirik W
authors.initials: SE
authors.lastname: Jacobsen
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005434:Flow Cytometry / Q000379:methods; D015870:Gene Expression; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D046228:Microarray Analysis; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D022423:Myeloid Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3