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The importance of dosage of core binding factors α and ß in hematopoietic development.

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Call No.	QP92 .T35 2005
Author	Talebian, Laleh.
Title	The importance of dosage of core binding factors α and ß in hematopoietic development.
Date	2005
Abstract	Core Binding Factors (CBFs) are members of a small family of transcription factors that play critical roles in a number of mammalian developmental processes. CBFs are heterodimers consisting of a CBFα subunit, which contacts and binds DNA at the core binding consensus sequence PyGPyGGT, and a non-DNA binding CBFß subunit, which binds the CBFα subunit and increases its affinity for DNA. Three genes ( RUNX1 or AML1, RUNX2 or AML3, and RUNX3 or AML2 ) encode the CBFß subunit, and one gene ( CBFB ) encodes CBFß. Haploinsufficiency of RUNX1 is associated with a familial platelet disorder that predisposes the affected individuals to developing Acute Myeloid Leukemia or FPD/AML. Haploinsufficiency of Runx1 in the mouse only partially mimics FPD/AML defects in humans, but dosage is important for several aspects of Runx1 in murine hematopoiesis (1) (2, 3). Haploinsufficiency of Runx2 results in severe defects in bone development and is the cause of a dominantly inherited disease called Cleidocranial Dysplasia or CCD in humans (4). Hypermethylation of the RUNX3 promoter or its hemizygous deletion results in significantly downregulated RUNX3 expression and is associated with human gastric cancer (5). CBFß is required for the functions of RUNX1 in hematopoiesis and RUNX2 in osteogenesis. Homozygous disruption of Cbfb in the mouse results in embryonic lethality at mid-gestation and a severe impairment of fetal liver hematopoiesis, a phenotype similar to Runx1 deficiency (1). To date, no developmental defects have been associated with lowered dosage of CBFß caused by haploinsufficiency or otherwise downregulated expression of Cbfb. The main focus of this thesis is to examine Cbfb requirements at later stages of hematopoiesis via the generation of a graded hypomorphic allelic series of Cbfb. This work provides evidence supporting new roles for Cbfb in mammalian hematopoietic development that are independent of Runx1 but involve other Runx family members. The final part of this thesis describes strategies used in generating a hypomorphic allelic series of Runx1 in an attempt to create a suitable mouse model for human FPD/AML.
Description	xv11, 172 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Nancy A. Speck
Subject	Hematopoiesis -- Regulation. ; Transcription factors.
College	Dartmouth Medical School -- Department of Biochemistry.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.1686

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