Myeloid leukemia with transdifferentiation plasticity developing from T-cell progenitors
Riemke P, Czeh M, Fischer J, Walter C, Ghani S, Zepper M, Agelopoulos K, Lettermann S, Gebhardt ML, Mah N, Weilemann A, Grau M, Gröning V, Haferlach T, Lenze D, Delwel R, Prinz M, Andrade-Navarro MA, Lenz G, Dugas M, Müller-Tidow C, Rosenbauer F.
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.
