First name
Giulia
Last name
De Conti
Year of Study
Research Center
Thesis Title
in vivo shRNA screening to identify quiescence-related genes required for AML growth
Thesis Abstract
AML is hierarchically organized with at the apex Leukemia Stem Cells (LSCs), a rare cell population
able to initiate and sustain the tumor growth. LSCs share many functional properties with normal
Hematopoietic Stem Cells (HSCs) including self-renewal capacity and quiescence. Quiescent LSCs
can survive to radiation and chemotherapy acting as a reservoir for leukemia relapse, the major cause
of death for AML patients. Therefore, LSCs quiescence is critical for leukemia maintenance and few
evidences suggest that quiescence regulation in pre-leukemic phase plays a pivotal role for
leukemogenic process as well.
In this work, we demonstrated that the expression of NPMc+ or PML-RARα in HSCs is sufficient to
enforce a quiescent stem cell gene expression profile. Therefore, we hypothesized that enhancement
of the quiescent phenotype in HSCs could be a shared mechanism for leukemia development and
maintenance. As an approach to examine the contribution of representative quiescence related genes
in AML, we exploited RNA interference technology to perform in vivo screening. Among the target
genes we found depleted during the screening, silencing of Stat1 or Sytl4 in AML blasts was sufficient
to significantly decrease in vitro self-renewal and delay leukemia growth in vivo.
able to initiate and sustain the tumor growth. LSCs share many functional properties with normal
Hematopoietic Stem Cells (HSCs) including self-renewal capacity and quiescence. Quiescent LSCs
can survive to radiation and chemotherapy acting as a reservoir for leukemia relapse, the major cause
of death for AML patients. Therefore, LSCs quiescence is critical for leukemia maintenance and few
evidences suggest that quiescence regulation in pre-leukemic phase plays a pivotal role for
leukemogenic process as well.
In this work, we demonstrated that the expression of NPMc+ or PML-RARα in HSCs is sufficient to
enforce a quiescent stem cell gene expression profile. Therefore, we hypothesized that enhancement
of the quiescent phenotype in HSCs could be a shared mechanism for leukemia development and
maintenance. As an approach to examine the contribution of representative quiescence related genes
in AML, we exploited RNA interference technology to perform in vivo screening. Among the target
genes we found depleted during the screening, silencing of Stat1 or Sytl4 in AML blasts was sufficient
to significantly decrease in vitro self-renewal and delay leukemia growth in vivo.
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