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MLL-AF9 Initiates Leukemic Transform...

Chen, Xinyue .

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MLL-AF9 Initiates Leukemic Transformation from Fast-Proliferating Myeloid Progenitors.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	MLL-AF9 Initiates Leukemic Transformation from Fast-Proliferating Myeloid Progenitors./
作者:	Chen, Xinyue .
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:	136 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-10, Section: B.
Contained By:	Dissertations Abstracts International81-10B.
標題:	Cellular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27540686
ISBN:	9798607315733

MLL-AF9 Initiates Leukemic Transformation from Fast-Proliferating Myeloid Progenitors.
Chen, Xinyue .

MLL-AF9 Initiates Leukemic Transformation from Fast-Proliferating Myeloid Progenitors. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 136 p.

Source: Dissertations Abstracts International, Volume: 81-10, Section: B.

Thesis (Ph.D.)--Yale University, 2019.

This item must not be sold to any third party vendors.

Cancer is a hyper-proliferative clonal disease. Whether the proliferative state originates from the cell-of-origin or emerges during disease progression remains elusive. In this thesis, I constructed an inducible acute myeloid leukemia (AML) mouse model mediated by oncogene MLL-AF9. By tracking de novo transformation from normal hematopoietic progenitors, I 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 provides permissiveness for transformation, with the fastest cycling 3% of GMPs acquiring malignancy with nearly 100% efficiency. Single cell RNA-seq analysis reveals that a naturally-existing subset of GMPs express low Ly6c2 and Csf1r but elevated levels of Cdk4/6, which are consistent with the cellular state most permissive to MLL-AF9 mediated transformation. Functionally, I 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. My work identifies a subset of primitive GMPs with extensive proliferation, and indicates that the fast proliferation states is a prerequisite for MLL-AF9 mediated transformation, rather than the consequence of malignant transformation. The mechanism for MLL-AF9 mediated transformation is likely conserved in humans, as the prognosis of MLL-fusion AMLs, but not other types of AMLs, can be stratified by the expression level of CCND1, a potential differentiation and cell cycle marker in human GMPs. My 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.

ISBN: 9798607315733Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

Cancer

MLL-AF9 Initiates Leukemic Transformation from Fast-Proliferating Myeloid Progenitors.
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520 $a Cancer is a hyper-proliferative clonal disease. Whether the proliferative state originates from the cell-of-origin or emerges during disease progression remains elusive. In this thesis, I constructed an inducible acute myeloid leukemia (AML) mouse model mediated by oncogene MLL-AF9. By tracking de novo transformation from normal hematopoietic progenitors, I 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 provides permissiveness for transformation, with the fastest cycling 3% of GMPs acquiring malignancy with nearly 100% efficiency. Single cell RNA-seq analysis reveals that a naturally-existing subset of GMPs express low Ly6c2 and Csf1r but elevated levels of Cdk4/6, which are consistent with the cellular state most permissive to MLL-AF9 mediated transformation. Functionally, I 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. My work identifies a subset of primitive GMPs with extensive proliferation, and indicates that the fast proliferation states is a prerequisite for MLL-AF9 mediated transformation, rather than the consequence of malignant transformation. The mechanism for MLL-AF9 mediated transformation is likely conserved in humans, as the prognosis of MLL-fusion AMLs, but not other types of AMLs, can be stratified by the expression level of CCND1, a potential differentiation and cell cycle marker in human GMPs. My 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.
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