MLL-AF9 initiates transformation from fast-proliferating myeloid progenitors


Chen XinyueORCID,Burkhardt Daniel B.ORCID,Hartman Amaleah A.,Hu Xiao,Eastman Anna E.,Sun Chao,Wang XujunORCID,Zhong Mei,Krishnaswamy SmitaORCID,Guo ShangqinORCID


AbstractCancer is a hyper-proliferative disease. Whether the proliferative state originates from the cell-of-origin or emerges later remains difficult to resolve. By tracking de novo transformation from normal hematopoietic progenitors expressing an acute myeloid leukemia (AML) oncogene MLL-AF9, we reveal that the cell cycle rate heterogeneity among granulocyte–macrophage progenitors (GMPs) determines their probability of transformation. A fast cell cycle intrinsic to these progenitors provide permissiveness for transformation, with the fastest cycling 3% GMPs acquiring malignancy with near certainty. Molecularly, we propose that MLL-AF9 preserves gene expression of the cellular states in which it is expressed. As such, when expressed in the naturally-existing, rapidly-cycling immature myeloid progenitors, this cell state becomes perpetuated, yielding malignancy. In humans, high CCND1 expression predicts worse prognosis for MLL fusion AMLs. Our work elucidates one of the earliest steps toward malignancy and suggests that modifying the cycling state of the cell-of-origin could be a preventative approach against malignancy.


U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

Gilead Sciences

Charles H. Hood Foundation


Springer Science and Business Media LLC


General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry







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