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

• Published in: Cell reports (Cambridge) Vol. 3; no. 6; pp. 1766 - 1776
• Main Authors: Mead, Adam J., Kharazi, Shabnam, Atkinson, Deborah, Macaulay, Iain, Pecquet, Christian, Loughran, Stephen, Lutteropp, Michael, Woll, Petter, Chowdhury, Onima, Luc, Sidinh, Buza-Vidas, Natalija, Ferry, Helen, Clark, Sally-Ann, Goardon, Nicolas, Vyas, Paresh, Constantinescu, Stefan N., Sitnicka, Ewa, Nerlov, Claus, Jacobsen, Sten Eirik W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.06.2013; Cell Press; Elsevier
• Subjects: Animals; Biologi; Biological Sciences; Cell Biology; Cell Differentiation - physiology; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cellbiologi; Disease Models, Animal; Flow Cytometry - methods; fms-Like Tyrosine Kinase 3 - genetics; fms-Like Tyrosine Kinase 3 - metabolism; fms-Like Tyrosine Kinase 3 - physiology; Gene Expression; Humans; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Medicin och hälsovetenskap; Mice; Microarray Analysis; Multipotent Stem Cells - cytology; Multipotent Stem Cells - immunology; Multipotent Stem Cells - metabolism; Multipotent Stem Cells - pathology; Myeloid Cells - cytology; Myeloid Cells - immunology; Myeloid Cells - metabolism; Myeloid Cells - pathology; Natural Sciences; Naturvetenskap; Signal Transduction
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.04.031

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. [Display omitted] •Flt3-ITDs collaborate with Runx1 mutation to cause acute myeloid leukemia exclusively•Flt3-ITDs instruct myeloid lineage bias in lymphoid-primed multipotent precursors•Flt3-ITDs inhibit thymic seeding by bone marrow progenitors•Flt3-ITD-induced myeloid bias and progenitor phenotype involve upregulation of Pu.1 In this study, Mead, Jacobsen, and colleagues demonstrate that constitutive growth factor receptor (GFR) signaling through an Flt3-ITD mutation instructs a myeloid-lineage differentiation bias to multipotent hematopoietic progenitor cells. Runx1 mutation collaborated with Flt3-ITD to induce aggressive, universally myeloid-lineage leukemias, indicating that Flt3-ITD GFR signaling acts to dictate the phenotype of resulting malignancies. The Flt3-ITD-induced myeloid lineage bias involves upregulation of the transcription factor Pu.1, thus establishing how GFR signaling might elicit lineage-instructive signaling in vivo.