FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors
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 t...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2013-06-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124713002131 |
| _version_ | 1828809966842019840 |
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| author | Adam J. Mead Shabnam Kharazi Deborah Atkinson Iain Macaulay Christian Pecquet Stephen Loughran Michael Lutteropp Petter Woll Onima Chowdhury Sidinh Luc Natalija Buza-Vidas Helen Ferry Sally-Ann Clark Nicolas Goardon Paresh Vyas Stefan N. Constantinescu Ewa Sitnicka Claus Nerlov Sten Eirik W. Jacobsen |
| author_facet | Adam J. Mead Shabnam Kharazi Deborah Atkinson Iain Macaulay Christian Pecquet Stephen Loughran Michael Lutteropp Petter Woll Onima Chowdhury Sidinh Luc Natalija Buza-Vidas Helen Ferry Sally-Ann Clark Nicolas Goardon Paresh Vyas Stefan N. Constantinescu Ewa Sitnicka Claus Nerlov Sten Eirik W. Jacobsen |
| author_sort | Adam J. Mead |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T09:04:46Z |
| format | Article |
| id | doaj.art-703445d2063749ebb29c59b6e36d5091 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-12T09:04:46Z |
| publishDate | 2013-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-703445d2063749ebb29c59b6e36d50912022-12-22T00:29:42ZengElsevierCell Reports2211-12472013-06-01361766177610.1016/j.celrep.2013.04.031FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent ProgenitorsAdam J. Mead0Shabnam Kharazi1Deborah Atkinson2Iain Macaulay3Christian Pecquet4Stephen Loughran5Michael Lutteropp6Petter Woll7Onima Chowdhury8Sidinh Luc9Natalija Buza-Vidas10Helen Ferry11Sally-Ann Clark12Nicolas Goardon13Paresh Vyas14Stefan N. Constantinescu15Ewa Sitnicka16Claus Nerlov17Sten Eirik W. Jacobsen18Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKHematopoietic Stem Cell Laboratory, Lund Stem Cell Center, Lund University, Lund 22184, SwedenHaematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKHaematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKLudwig Institute for Cancer Research, Brussels B1200, BelgiumHaematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKHaematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKHaematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKHaematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKHaematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKHaematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKHaematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKHaematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKMRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKMRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKLudwig Institute for Cancer Research, Brussels B1200, BelgiumHematopoietic Stem Cell Laboratory, Lund Stem Cell Center, Lund University, Lund 22184, SwedenMRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKHaematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKWhether 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.http://www.sciencedirect.com/science/article/pii/S2211124713002131 |
| spellingShingle | Adam J. Mead Shabnam Kharazi Deborah Atkinson Iain Macaulay Christian Pecquet Stephen Loughran Michael Lutteropp Petter Woll Onima Chowdhury Sidinh Luc Natalija Buza-Vidas Helen Ferry Sally-Ann Clark Nicolas Goardon Paresh Vyas Stefan N. Constantinescu Ewa Sitnicka Claus Nerlov Sten Eirik W. Jacobsen FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors Cell Reports |
| title | FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors |
| title_full | FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors |
| title_fullStr | FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors |
| title_full_unstemmed | FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors |
| title_short | FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors |
| title_sort | flt3 itds instruct a myeloid differentiation and transformation bias in lymphomyeloid multipotent progenitors |
| url | http://www.sciencedirect.com/science/article/pii/S2211124713002131 |
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