MLL-AF9 initiates transformation from fast-proliferating myeloid progenitors

Xinyue Chen, Daniel B. Burkhardt, Amaleah A. Hartman, Xiao Hu, Anna E. Eastman, Chao Sun, Xujun Wang, Mei Zhong, Smita Krishnaswamy and Shangqin Guo ()
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Xinyue Chen: Yale University
Daniel B. Burkhardt: Yale University
Amaleah A. Hartman: Yale University
Xiao Hu: Yale University
Anna E. Eastman: Yale University
Chao Sun: Yale University
Xujun Wang: Shanghai Jiao Tong University
Mei Zhong: Yale University
Smita Krishnaswamy: Yale University
Shangqin Guo: Yale University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Cancer 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.

Date: 2019
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DOI: 10.1038/s41467-019-13666-5

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