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Myeloid leukemia with transdifferentiation plasticity developing from T‐cell progenitors
Author(s) -
Riemke Pia,
Czeh Melinda,
Fischer Josephine,
Walter Carolin,
Ghani Saeed,
Zepper Matthias,
Agelopoulos Konstantin,
Lettermann Stephanie,
Gebhardt Marie L,
Mah Nancy,
Weilemann Andre,
Grau Michael,
Gröning Verena,
Haferlach Torsten,
Lenze Dido,
Delwel Ruud,
Prinz Marco,
AndradeNavarro Miguel A,
Lenz Georg,
Dugas Martin,
MüllerTidow Carsten,
Rosenbauer Frank
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201693927
Subject(s) - biology , transdifferentiation , myeloid leukemia , progenitor cell , progenitor , leukemia , myeloid , microbiology and biotechnology , cancer research , immunology , stem cell
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.