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Discovering MII1 regulated pathways in hematopoietic stem cells.

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Author	Artinger, Erika L.
Title	Discovering MII1 regulated pathways in hematopoietic stem cells.
Date	2012
Abstract	Hematopoietic stem cells (HSCs) balance self-renewal with the continuous production of the suitable numbers of lineage-restricted progenitor cells. In this work we demonstrate that the Mixed lineage leukemia 1 (Mll1) gene is essential for this process. Mll1, a Trithorax homolog that encodes a chromatin modifying protein, was originally identified as a proto-oncogene. Oncogenic fusion proteins formed by translocations that fuse Mll1 to one of several partner genes are thought result in leukemia because they co-opt the normal functions of wild-type Mll1. Through the use of a conditional loss-of-function allele, we have established that deletion of wild-type Mll1 in an adult mouse results in rapid depletion of HSC activity and subsequent lethal bone marrow cytopenia. Surprisingly, this cell loss is accompanied by a cell-intrinsic increase in proliferation within the HSC population. To better understand the underlying mechanisms through which Mll1 regulates stem self-renewal and proliferation, we assayed the global gene expression profiles of Mll1-deficient HSCs. This analysis identified a set of up-regulated genes associated with proliferation, mitochondrial biogenesis, and erythroid lineage specification. Transcriptional regulators with important roles in hematopoiesis comprised a large proportion of Mll1-dependent genes, including Hoxa9, Mecom, Eya1, Pbx1 and Prdm16. These genes are HSC-specific, direct targets of Mll1 that function primarily in independent pathways. This work identifies a transcriptional network that expands our understanding of Mll1 gene regulation beyond the known Hox target genes and provides a framework for dissecting the differential actions of wild-type Mll1 and oncogenic Mll1-fusion genes in normal stem cell homeostasis and leukemia.
Description	1 online resource (xi, 204 leaves) : illustrations (some color)
Format	application/pdf
Advisor	Ernst, Patricia A. ; Gorham, James D. ; DiRenzo, James ; Perkins, Archibald S.
Subject	Hematopoietic stem cells. ; Hematopoietic stem cell disorders -- Genetic aspects. ; Genetic transcription -- Regulation. ; Leukemia -- Genetic aspects. ; Cell proliferation. ; Myeloid-Lymphoid Leukemia Protein -- genetics.
College	Dartmouth Medical School -- Department of Genetics.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D)--Dartmouth College.
Copyright	In Copyright. This material is protected by copyright and/or related rights. You are free to use this material in any way that is permitted by copyright law that applies to your use. For other uses, you need to obtain permission from the rights-holder(s). http://rightsstatements.org/page/InC/1.0/
DOI	https://doi.org/10.1349/ddlp.2655

Title	artinger2012 1
Full Text	i Discovering Mll1 Regulated Pathways in Hematopoietic Stem Cells A Thesis Submitted to the Faculty In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Genetics by Erika L. Artinger DARTMOUTH COLLEGE Hanover, New Hampshire January 1st, 2012

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Discovering MII1 regulated pathways in hematopoietic stem cells.

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