title: Myeloid leukemia with transdifferentiation plasticity developing from T-cell progenitors.
abstract: Unfavorable patient survival coincides with lineage plasticity observed in human acute leukemias. These cases are assumed to arise from hematopoietic stem cells, which have stable multipotent differentiation potential. However, here we report that plasticity in leukemia can result from instable lineage identity states inherited from differentiating progenitor cells. Using mice with enhanced c-Myc expression, we show, at the single-cell level, that T-lymphoid progenitors retain broad malignant lineage potential with a high capacity to differentiate into myeloid leukemia. These T-cell-derived myeloid blasts retain expression of a defined set of T-cell transcription factors, creating a lymphoid epigenetic memory that confers growth and propagates myeloid/T-lymphoid plasticity. Based on these characteristics, we identified a correlating human leukemia cohort and revealed targeting of Jak2/Stat3 signaling as a therapeutic possibility. Collectively, our study suggests the thymus as a source for myeloid leukemia and proposes leukemic plasticity as a driving mechanism. Moreover, our results reveal a pathway-directed therapy option against thymus-derived myeloid leukemogenesis and propose a model in which dynamic progenitor differentiation states shape unique neoplastic identities and therapy responses.
authors: Institute of Molecular Tumor Biology, University of Münster, Münster, Germany.
authors: Pia
authors: P
authors: Riemke
authors: Institute of Molecular Tumor Biology, University of Münster, Münster, Germany.
authors: Melinda
authors: M
authors: Czeh
authors: Institute of Molecular Tumor Biology, University of Münster, Münster, Germany.
authors: Josephine
authors: J
authors: Fischer
authors: Institute of Medical Informatics, University of Münster, Münster, Germany.
authors: Carolin
authors: C
authors: Walter
authors: Department of Hematology, Oncology, and Tumor Immunology, Robert-Rössle-Clinic, Berlin, Germany.
authors: Saeed
authors: S
authors: Ghani
authors: Institute of Molecular Tumor Biology, University of Münster, Münster, Germany.
authors: Matthias
authors: M
authors: Zepper
authors: Department of Dermatology, Competence Center Chronic Pruritus University of Münster, Münster, Germany.
authors: Konstantin
authors: K
authors: Agelopoulos
authors: Molecular Hematology and Oncology, Medical Clinics A, University of Münster, Münster, Germany.
authors: Stephanie
authors: S
authors: Lettermann
authors: Department of Computational Biology and Data Mining, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors: Marie L
authors: ML
authors: Gebhardt
authors: Berlin-Brandenburger Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors: Nancy
authors: N
authors: Mah
authors: Translational Oncology, Medical Clinics A, University of Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors: Andre
authors: A
authors: Weilemann
authors: Translational Oncology, Medical Clinics A, University of Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors: Michael
authors: M
authors: Grau
authors: Institute of Molecular Tumor Biology, University of Münster, Münster, Germany.
authors: Verena
authors: V
authors: Gröning
authors: MLL Munich Leukemia Laboratory, Munich, Germany.
authors: Torsten
authors: T
authors: Haferlach
authors: Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors: Dido
authors: D
authors: Lenze
authors: Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Ruud
authors: R
authors: Delwel
authors: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.|BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
authors: Marco
authors: 0000-0002-0349-1955
authors: M
authors: Prinz
authors: Department of Medical Informatics and Biomathematics, Institute of Molecular Biology Johannes Gutenberg University of Mainz, Mainz, Germany.
authors: Miguel A
authors: MA
authors: Andrade-Navarro
authors: Translational Oncology, Medical Clinics A, University of Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors: Georg
authors: G
authors: Lenz
authors: Institute of Medical Informatics, University of Münster, Münster, Germany.
authors: Martin
authors: M
authors: Dugas
authors: Department of Internal Medicine, Hematology and Oncology, University of Halle-Wittenberg, Halle, Germany.
authors: Carsten
authors: C
authors: Müller-Tidow
authors: Institute of Molecular Tumor Biology, University of Münster, Münster, Germany frank.rosenbauer@ukmuenster.de.
authors: Frank
authors: 0000-0001-7977-9421
authors: F
authors: Rosenbauer
mesh_terms: D000818:Animals; D054338:Cell Transdifferentiation; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D054503:Lymphoid Progenitor Cells / Q000502:physiology*; D051379:Mice; D013601:T-Lymphocytes / Q000502:physiology*
keywords: T‐cell progenitors; leukemia; lineage plasticity; myeloid differentiation