CSF3R T618I Collaborates With RUNX1-RUNX1T1 to Expand Hematopoietic Progenitors and Sensitizes to GLI Inhibition
Activating colony-stimulating factor-3 receptor gene (CSF3R) mutations are recurrent in acute myeloid leukemia (AML) with t(8;21) translocation. However, the nature of oncogenic collaboration between alterations of CSF3R and the t(8;21) associated RUNX1-RUNX1T1 fusion remains unclear. In CD34+ hemat...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-10-01
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| Series: | HemaSphere |
| Online Access: | http://journals.lww.com/10.1097/HS9.0000000000000958 |
| _version_ | 1827331532180684800 |
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| author | Anja S. Swoboda Vanessa C. Arfelli Anna Danese Roland Windisch Paul Kerbs Enric Redondo Monte Johannes W. Bagnoli Linping Chen-Wichmann Alessandra Caroleo Monica Cusan Stefan Krebs Helmut Blum Michael Sterr Wolfgang Enard Tobias Herold Maria Colomé-Tatché Christian Wichmann Philipp A. Greif |
| author_facet | Anja S. Swoboda Vanessa C. Arfelli Anna Danese Roland Windisch Paul Kerbs Enric Redondo Monte Johannes W. Bagnoli Linping Chen-Wichmann Alessandra Caroleo Monica Cusan Stefan Krebs Helmut Blum Michael Sterr Wolfgang Enard Tobias Herold Maria Colomé-Tatché Christian Wichmann Philipp A. Greif |
| author_sort | Anja S. Swoboda |
| collection | DOAJ |
| description | Activating colony-stimulating factor-3 receptor gene (CSF3R) mutations are recurrent in acute myeloid leukemia (AML) with t(8;21) translocation. However, the nature of oncogenic collaboration between alterations of CSF3R and the t(8;21) associated RUNX1-RUNX1T1 fusion remains unclear. In CD34+ hematopoietic stem and progenitor cells from healthy donors, double oncogene expression led to a clonal advantage, increased self-renewal potential, and blast-like morphology and distinct immunophenotype. Gene expression profiling revealed hedgehog signaling as a potential mechanism, with upregulation of GLI2 constituting a putative pharmacological target. Both primary hematopoietic cells and the t(8;21) positive AML cell line SKNO-1 showed increased sensitivity to the GLI inhibitor GANT61 when expressing CSF3R T618I. Our findings suggest that during leukemogenesis, the RUNX1-RUNXT1 fusion and CSF3R mutation act in a synergistic manner to alter hedgehog signaling, which can be exploited therapeutically. |
| first_indexed | 2024-03-07T16:37:36Z |
| format | Article |
| id | doaj.art-94becda414dc465bba3fb42b380085d1 |
| institution | Directory Open Access Journal |
| issn | 2572-9241 |
| language | English |
| last_indexed | 2024-03-07T16:37:36Z |
| publishDate | 2023-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | HemaSphere |
| spelling | doaj.art-94becda414dc465bba3fb42b380085d12024-03-03T09:26:58ZengWileyHemaSphere2572-92412023-10-01710e95810.1097/HS9.0000000000000958202310000-00014CSF3R T618I Collaborates With RUNX1-RUNX1T1 to Expand Hematopoietic Progenitors and Sensitizes to GLI InhibitionAnja S. Swoboda0Vanessa C. Arfelli1Anna Danese2Roland Windisch3Paul Kerbs4Enric Redondo Monte5Johannes W. Bagnoli6Linping Chen-Wichmann7Alessandra Caroleo8Monica Cusan9Stefan Krebs10Helmut Blum11Michael Sterr12Wolfgang Enard13Tobias Herold14Maria Colomé-Tatché15Christian Wichmann16Philipp A. Greif171 Department of Medicine III, University Hospital, LMU Munich, Germany1 Department of Medicine III, University Hospital, LMU Munich, Germany4 Computational Health Center, Helmholtz Center Munich, Neuherberg, Germany6 Division of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital, LMU Munich, Germany1 Department of Medicine III, University Hospital, LMU Munich, Germany1 Department of Medicine III, University Hospital, LMU Munich, Germany7 Anthropology and Human Genomics, Faculty of Biology, LMU Munich, Martinsried, Germany6 Division of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital, LMU Munich, Germany1 Department of Medicine III, University Hospital, LMU Munich, Germany1 Department of Medicine III, University Hospital, LMU Munich, Germany8 Gene Center - Laboratory for Functional Genome Analysis, LMU Munich, Germany8 Gene Center - Laboratory for Functional Genome Analysis, LMU Munich, Germany9 Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany7 Anthropology and Human Genomics, Faculty of Biology, LMU Munich, Martinsried, Germany1 Department of Medicine III, University Hospital, LMU Munich, Germany4 Computational Health Center, Helmholtz Center Munich, Neuherberg, Germany6 Division of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital, LMU Munich, Germany1 Department of Medicine III, University Hospital, LMU Munich, GermanyActivating colony-stimulating factor-3 receptor gene (CSF3R) mutations are recurrent in acute myeloid leukemia (AML) with t(8;21) translocation. However, the nature of oncogenic collaboration between alterations of CSF3R and the t(8;21) associated RUNX1-RUNX1T1 fusion remains unclear. In CD34+ hematopoietic stem and progenitor cells from healthy donors, double oncogene expression led to a clonal advantage, increased self-renewal potential, and blast-like morphology and distinct immunophenotype. Gene expression profiling revealed hedgehog signaling as a potential mechanism, with upregulation of GLI2 constituting a putative pharmacological target. Both primary hematopoietic cells and the t(8;21) positive AML cell line SKNO-1 showed increased sensitivity to the GLI inhibitor GANT61 when expressing CSF3R T618I. Our findings suggest that during leukemogenesis, the RUNX1-RUNXT1 fusion and CSF3R mutation act in a synergistic manner to alter hedgehog signaling, which can be exploited therapeutically.http://journals.lww.com/10.1097/HS9.0000000000000958 |
| spellingShingle | Anja S. Swoboda Vanessa C. Arfelli Anna Danese Roland Windisch Paul Kerbs Enric Redondo Monte Johannes W. Bagnoli Linping Chen-Wichmann Alessandra Caroleo Monica Cusan Stefan Krebs Helmut Blum Michael Sterr Wolfgang Enard Tobias Herold Maria Colomé-Tatché Christian Wichmann Philipp A. Greif CSF3R T618I Collaborates With RUNX1-RUNX1T1 to Expand Hematopoietic Progenitors and Sensitizes to GLI Inhibition HemaSphere |
| title | CSF3R T618I Collaborates With RUNX1-RUNX1T1 to Expand Hematopoietic Progenitors and Sensitizes to GLI Inhibition |
| title_full | CSF3R T618I Collaborates With RUNX1-RUNX1T1 to Expand Hematopoietic Progenitors and Sensitizes to GLI Inhibition |
| title_fullStr | CSF3R T618I Collaborates With RUNX1-RUNX1T1 to Expand Hematopoietic Progenitors and Sensitizes to GLI Inhibition |
| title_full_unstemmed | CSF3R T618I Collaborates With RUNX1-RUNX1T1 to Expand Hematopoietic Progenitors and Sensitizes to GLI Inhibition |
| title_short | CSF3R T618I Collaborates With RUNX1-RUNX1T1 to Expand Hematopoietic Progenitors and Sensitizes to GLI Inhibition |
| title_sort | csf3r t618i collaborates with runx1 runx1t1 to expand hematopoietic progenitors and sensitizes to gli inhibition |
| url | http://journals.lww.com/10.1097/HS9.0000000000000958 |
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