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Updated: May 10, 2026
Pan-myeloid Differentiation of Human Cord Blood Derived CD34+ Hematopoietic Stem and Progenitor Cells
Published on: August 9, 2019
FLT3-ITDs instruct a myeloid differentiation and transformation bias in lymphomyeloid multipotent progenitors
Adam J Mead1, Shabnam Kharazi, Deborah Atkinson
1Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. adam.mead@imm.ox.ac.uk
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.
Insights
Gain-of-function Flt3-ITD mutations in multipotent progenitors (MPPs) collaborate with Runx1 mutations to cause aggressive myeloid leukemias. Aberrant growth factor receptor signaling drives myeloid lineage bias in MPPs.
Area of Science:
- Hematopoiesis
- Cancer Biology
- Molecular Signaling
Background:
- The role of growth factor receptor (GFR) signaling in multipotent progenitor (MPP) lineage fate determination remains unclear.
- FLT3-ITD mutations are paradoxically linked to acute myeloid leukemia (AML) despite FLT3's typical role in lymphoid development.
Purpose of the Study:
- To investigate how aberrant GFR signaling, specifically Flt3-ITD mutations, influences lineage commitment in MPPs.
- To elucidate the mechanisms by which Flt3-ITD mutations contribute to myeloid leukemia development.
Main Methods:
- Utilized a mouse knockin model with a gain-of-function Flt3-ITD mutation.
- Analyzed the collaborative effects of Flt3-ITD and Runx1 mutations on hematopoietic stem and progenitor cells.
- Examined transcriptional changes and lineage bias in MPPs.
Main Results:
- Flt3-ITD collaborated with Runx1 mutation to induce aggressive myeloid leukemias with high penetrance.
- Flt3-ITDs promoted MPP expansion with reduced lymphoid and increased myeloid transcriptional priming.
- Early B and T lymphopoiesis were compromised, and myeloid lineage bias was linked to Pu.1 upregulation via Stat3 signaling.
Conclusions:
- Aberrant GFR signaling, exemplified by Flt3-ITDs, can inflict myeloid lineage bias on MPPs.
- Oncogenic mutations can subvert normal lineage commitment processes, dictating malignancy phenotype.
- Findings offer insights into the pathogenesis of myeloid leukemias driven by GFR mutations.
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01:15Differentiation of Common Myeloid Progenitor Cells
01:21Lineage Commitment