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Structural and functional characterization of Runx1 point mutations identified in leukemia and cleidocranial dysplasia patients.

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Call No.	QP552.T68 M38 2005
Author	Matheny, Christina.
Title	Structural and functional characterization of Runx1 point mutations identified in leukemia and cleidocranial dysplasia patients.
Date	2005
Abstract	Core binding factors are heterodimeric transcription factors involved in diverse developmental processes. They consist of a DNA binding Runx subunit and a non-DNA binding CBFβ sub-unit. Runx proteins are encoded by three genes: Runx1, Runx2 , and Runx3 while Cbfβ is encoded by one gene, Cbfb. Runx1 is required at multiple stages of hematopoiesis, and is frequently mutated in leukemia. Runx2 is required for both osteoblast differentiation and chondrocyte hypertrophy in bone development. Deletion, nonsense, frameshift, and missense mutations in RUNX1 and RUNX2 have all been associated with disease. More recently point mutations have been identified in the runt domain of these proteins associated with disease. These monoallelic mutations in RUNX1 are associated with the hemotopoietic disorders familial platelet disorder with predisposition for acute myelogenous leukemia (FPD/AML) and myelodysplastic syndrome (MDS), while biallelic mutations are associated with the most immature undifferentiated from of acute myeloid leukemia (AML M0). Patients with monoallelic mutations in RUNX2 have the skeletal disorder cleidocranial dysplasia (CCD). FPD/AML and CCD pedigrees have revealed varying degrees of disease severity depending on the nature of the specific mutation. Additionally, it has been observed that mutations involving amino acids in the DNA binding Runt domain that directly contact DNA are associated primarily with hematopoietic disorders, while mutations predicted to disrupt CBFβ binding or the Runt domain structure are found only in CCD patients. The biochemical and biophysical effects of twenty-six Runx1 Runt domain amino acid substitutions identified in FPD/AML, AML M0, and CCD patients were quantified. Their effects on DNA binding, heterodimerization with CBFβ, and the Runt domain structure were analyzed using yeast one- and two-hybrid, quantitative electrophoretic mobility shift, heteronuclear single quantum correlation spectroscopy, and urea denaturation experiments. To address the impact on in vivo function, several of these point mutations were engineered into the endogenous Runx1 allele in mice. These five mutations include: R177X, R174Q, T149A, T161A, and L148F. R177X is found in FPD/AML patients and truncates Runx1 immediately C-terminal to the Runt domain. R174Q (found in FPD/AML and CCD) disrupts DNA binding 1000-fold, but does not disrupt CBFβ binding or perturb the Runt domain fold.
Description	xii, 137 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Jennifer Loros.
Subject	Transcription factors -- Pathophysiology. Hematopoiesis -- Genetic aspects. Genetic transcription -- Regulation. DNA-binding proteins. Leukemia -- Genetic aspects. Core Binding Factor Alpha 2 Subunit. Core Binding Factor beta Subunit. Cleidocranial Dysplasia -- genetics.
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.97

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	Structural and Functional Characterization of Runx1 Point Mutations Identified in Leukemia and Cleidocranial Dysplasia Patients A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biochemistry by Christina Matheny Dartmouth College Hanover, New Hampshire August 24, 2005 Examination Committee _____________________ Jennifer Loros (chair) _____________________ _____________________ Amy Anderson Charles Barlowe Dean of Graduate Studies _____________________ Nancy Speck _____________________ Lucio Castilla

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