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.
See also: L Bullinger (November 2016)
The inherent lineage plasticity of multipotent hematopoietic stem cells is thought to be causal for the development of human acute myeloid leukemia (AML). Here, early non‐committed lymphoid progenitors are shown to give rise to myeloid blasts, which retain epigenetic cell‐of‐origin memory and are promoted by Jak/Stat signaling.
Myc/Bcl2‐transformed mouse early T‐cell progenitors have broad malignant lineage potential and can generate myeloid leukemic progeny in in vitro colony formation and in vivo transplantation assays.
T‐cell progenitor‐derived myeloid leukemia cells express a lymphoid epigenetic memory that confers growth and propagates myeloid/T‐lymphoid plasticity.
A cohort of ˜5% human AML cases resembles mouse T‐cell‐derived leukemia and thus may be of thymic origin.
Jak2/Stat3 signaling is required for proliferation of T‐cell progenitor‐derived myeloid leukemia cells and leukemogenesis in vivo.
The EMBO Journal (2016) 35: 2399–2416
- Received January 21, 2016.
- Revision received July 25, 2016.
- Accepted July 27, 2016.
- © 2016 The Authors