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Myeloid leukemia with transdifferentiation plasticity developing from T-cell progenitors

Item Type:Article
Title:Myeloid leukemia with transdifferentiation plasticity developing from T-cell progenitors
Creators Name:Riemke, P. and Czeh, M. and Fischer, J. and Walter, C. and Ghani, S. and Zepper, M. and Agelopoulos, K. and Lettermann, S. and Gebhardt, M.L. and Mah, N. and Weilemann, A. and Grau, M. and Groening, V. and Haferlach, T. and Lenze, D. and Delwel, R. and Prinz, M. and Andrade-Navarro, M.A. and Lenz, G. and Dugas, M. and Mueller-Tidow, C. and Rosenbauer, F.
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.
Keywords:Leukemia, Lineage Plasticity, Myeloid Differentiation, T‐Cell Progenitors, Animals, Mice
Source:EMBO Journal
ISSN:0261-4189
Publisher:EMBO Press (U.S.A.)
Volume:35
Number:22
Page Range:2399-2416
Date:15 November 2016
Official Publication:https://doi.org/10.15252/embj.201693927
PubMed:View item in PubMed

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