EFFECTS OF ACTIVATING MUTATIONS IN SHP-2 (PTPN11) PHOSPHATASE ON HEMATOPOIETIC CELL DEVELOPMENT

Bibliographic Details
Main Author:	Xu, Dan
Language:	English
Published:	Case Western Reserve University School of Graduate Studies / OhioLINK 2011
Subjects:	Biology
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=case1295052361

id	ndltd-OhioLink-oai-etd.ohiolink.edu-case1295052361
record_format	oai_dc
spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-case12950523612021-08-03T05:33:51Z EFFECTS OF ACTIVATING MUTATIONS IN SHP-2 (PTPN11) PHOSPHATASE ON HEMATOPOIETIC CELL DEVELOPMENT Xu, Dan Biology Germline and somatic gain-of-function mutations in the tyrosine phosphatase PTPN11 (Shp-2) are associated with juvenile myelomonocytic leukemia (JMML), a myeloproliferative disease (MPD) of early childhood, which often progresses to blast crisis/overt leukemia. In my study, I have demonstrated that germline mutation Ptpn11D61G in mice aberrantly accelerates hematopoietic stem cell (HSC) cycling, increases stem cell pool, and elevates short-term and long-term repopulating capabilities, leading to the development of MPD. The MPD is reproduced in primary and secondary recipient mice transplanted with Ptpn11D61G/+ whole bone marrow cells or purified Lineage- Sca-1+c-Kit+ cells, but not lineage committed progenitors. The pathogenic effects of Ptpn11D61G mutation on HSCs are attributable to enhanced cytokine/growth factor signaling. The aberrant HSC activities caused by Ptpn11D61G mutation are largely corrected by deletion of Gab2, a Shp-2 interacting protein/target that plays an essential role in cell signaling. More importantly, MPD phenotypes are markedly ameliorated in Ptpn11D61G/+/Gab2-/- double mutant mice. Together, these studies suggest that oncogenic Ptpn11 induces MPD by aberrant activation of HSCs and identify Gab2 as an important mediator for the pathogenic effects of Ptpn11 mutations. In my another study, we created a conditional knock-in mouse model with the most common and the most potent PTPN11 activating mutation (E76K) found in JMML. Unlike Ptpn11D61G mutation, Ptpn11E76K mutation evokes frank T cell lymphoid leukemia/lymphoma (T-ALL), acute myeloid leukemia (AML) and B cell lymphoid leukemia (B-ALL) with full penetrance following a chronic phase of MPD. Ptpn11E76K mutation aberrantly activates hematopoietic stem cells (HSCs) and lineage progenitors by enhancing growth factor/cytokine signaling. Remarkably, Ptpn11E76K mutation induces leukemia-initiating/propagating cell development not only in HSCs but also in lineage committed progenitors. These findings reveal non-lineage specific effects of Ptpn11E76K mutation on malignant transformation of JMML and provide the first evidence that an activating mutation in Ptpn11 phosphatase plays a causal role in malignant leukemias. The unique disease evolution pattern of Ptpn11E76K knock-in mice represents the natural course of JMML. The novel Ptpn11E76K mouse model will be valuable for studying disease progression and preclinical trials aiming at controlling malignant transformation in JMML. 2011 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1295052361 http://rave.ohiolink.edu/etdc/view?acc_num=case1295052361 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Biology
spellingShingle	Biology Xu, Dan EFFECTS OF ACTIVATING MUTATIONS IN SHP-2 (PTPN11) PHOSPHATASE ON HEMATOPOIETIC CELL DEVELOPMENT
author	Xu, Dan
author_facet	Xu, Dan
author_sort	Xu, Dan
title	EFFECTS OF ACTIVATING MUTATIONS IN SHP-2 (PTPN11) PHOSPHATASE ON HEMATOPOIETIC CELL DEVELOPMENT
title_short	EFFECTS OF ACTIVATING MUTATIONS IN SHP-2 (PTPN11) PHOSPHATASE ON HEMATOPOIETIC CELL DEVELOPMENT
title_full	EFFECTS OF ACTIVATING MUTATIONS IN SHP-2 (PTPN11) PHOSPHATASE ON HEMATOPOIETIC CELL DEVELOPMENT
title_fullStr	EFFECTS OF ACTIVATING MUTATIONS IN SHP-2 (PTPN11) PHOSPHATASE ON HEMATOPOIETIC CELL DEVELOPMENT
title_full_unstemmed	EFFECTS OF ACTIVATING MUTATIONS IN SHP-2 (PTPN11) PHOSPHATASE ON HEMATOPOIETIC CELL DEVELOPMENT
title_sort	effects of activating mutations in shp-2 (ptpn11) phosphatase on hematopoietic cell development
publisher	Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate	2011
url	http://rave.ohiolink.edu/etdc/view?acc_num=case1295052361
work_keys_str_mv	AT xudan effectsofactivatingmutationsinshp2ptpn11phosphataseonhematopoieticcelldevelopment
_version_	1719421806060765184

EFFECTS OF ACTIVATING MUTATIONS IN SHP-2 (PTPN11) PHOSPHATASE ON HEMATOPOIETIC CELL DEVELOPMENT

Similar Items