DOI: 10.1101/484220Nov 30, 2018Paper

MLL-AF9 Initiates Transformation From Fast-Proliferating Myeloid Progenitors

BioRxiv : the Preprint Server for Biology
Xinyue ChenShangqin Guo

Abstract

Cancer is a hyper-proliferative clonal disease. Whether the proliferative state originates from the cell-of-origin or emerges later remains elusive. 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. An intrinsic fast cell cycle kinetics at the time of oncogene expression provide permissiveness for transformation, with the fastest cycling 3% of GMPs (~0.006% of bone marrow nucleated cells) acquiring malignancy with nearly 100% efficiency. Molecularly, we propose that MLL-AF9 preserves the gene expression of the cellular states in which it is expressed. As such, when expressed in the naturally-existing, rapidly-cycling myeloid progenitors, this cell state is perpetuated, yielding malignancy. Our work elucidates one of the earliest steps toward malignancy and suggests that modifying the cycling state of the cell-of-origin could be an effective approach to prevent malignancy.

Related Concepts

Malignant Neoplasms
Cell Cycle
Gene Expression
Hematopoietic Stem Cells
Leukemia, Myelocytic, Acute
Macrophage
Transformation, Genetic
Hyperactive Behavior
Cell Proliferation
Myeloid Progenitor Cells

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