Hematopoietic colony formation from human growth factor-dependent TF1 cells and human cord blood myeloid progenitor cells depends on shp2 phosphatase function

Hal Broxmeyer, Maryse Etienne-Julan, Akihiko Gotoh, Stephen E. Braun, Li Lu, Scott Cooper, Gen Sheng Feng, Xing Jun Li, Rebecca Chan

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The protein tyrosine phosphatase, SHP2, is widely expressed; however, previous studies demonstrated that hematopoietic cell development more stringently requires Shp2 expression compared to other tissues. Furthermore, somatic gain-of-function SHP2 mutants are commonly found in human myeloid leukemias. Given that pharmacologic inhibitors to SHP2 phosphatase activity are currently in development as putative antileukemic agents, we conducted a series of experiments examining the necessity of SHP2 phosphatase activity for human hematopoiesis. Anti-sense oligonucleotides to human SHP2 coding sequences reduced human cord blood- and human cell line, TF1-derived colony formation. Expression of truncated SHP2 bearing its Src homology 2 (SH2) domains, but lacking the phosphatase domain similarly reduced human cord blood- and TF1-derived colony formation. Mechanistically, expression of truncated SHP2 reduced the interaction between endogenous, full-length SHP2 with the adapter protein, Grb2. To verify the role of SHP2 phosphatase function in human hematopoietic cell development, human cord blood CD34+ cells were transduced with a leukemia-associated phosphatase gain-of-function SHP2 mutant or with a phosphatase dead SHP2 mutant, which indicated that increased phosphatase function enhanced, while decreased SHP2 phosphatase function reduced, human cord blood-derived colonies. Collectively, these findings indicate that SHP2 phosphatase function regulates human hematopoietic cell development and imply that the phosphatase component of SHP2 may serve as a pharmacologic target in human leukemias bearing increased SHP2 phosphatase activity.

Original languageEnglish
Pages (from-to)998-1006
Number of pages9
JournalStem Cells and Development
Volume22
Issue number6
DOIs
StatePublished - Mar 15 2013

Fingerprint

Non-Receptor Type 11 Protein Tyrosine Phosphatase
Myeloid Progenitor Cells
Fetal Blood
Phosphoric Monoester Hydrolases
Blood Cells
Intercellular Signaling Peptides and Proteins
Leukemia
Protein Tyrosine Phosphatases
Myeloid Leukemia
src Homology Domains
Antisense Oligonucleotides
Hematopoiesis
Human Development
Human Activities

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Hematology

Cite this

Hematopoietic colony formation from human growth factor-dependent TF1 cells and human cord blood myeloid progenitor cells depends on shp2 phosphatase function. / Broxmeyer, Hal; Etienne-Julan, Maryse; Gotoh, Akihiko; Braun, Stephen E.; Lu, Li; Cooper, Scott; Feng, Gen Sheng; Li, Xing Jun; Chan, Rebecca.

In: Stem Cells and Development, Vol. 22, No. 6, 15.03.2013, p. 998-1006.

Research output: Contribution to journalArticle

Broxmeyer, Hal ; Etienne-Julan, Maryse ; Gotoh, Akihiko ; Braun, Stephen E. ; Lu, Li ; Cooper, Scott ; Feng, Gen Sheng ; Li, Xing Jun ; Chan, Rebecca. / Hematopoietic colony formation from human growth factor-dependent TF1 cells and human cord blood myeloid progenitor cells depends on shp2 phosphatase function. In: Stem Cells and Development. 2013 ; Vol. 22, No. 6. pp. 998-1006.
@article{876f5549e636400fbc161d0946ccc3b5,
title = "Hematopoietic colony formation from human growth factor-dependent TF1 cells and human cord blood myeloid progenitor cells depends on shp2 phosphatase function",
abstract = "The protein tyrosine phosphatase, SHP2, is widely expressed; however, previous studies demonstrated that hematopoietic cell development more stringently requires Shp2 expression compared to other tissues. Furthermore, somatic gain-of-function SHP2 mutants are commonly found in human myeloid leukemias. Given that pharmacologic inhibitors to SHP2 phosphatase activity are currently in development as putative antileukemic agents, we conducted a series of experiments examining the necessity of SHP2 phosphatase activity for human hematopoiesis. Anti-sense oligonucleotides to human SHP2 coding sequences reduced human cord blood- and human cell line, TF1-derived colony formation. Expression of truncated SHP2 bearing its Src homology 2 (SH2) domains, but lacking the phosphatase domain similarly reduced human cord blood- and TF1-derived colony formation. Mechanistically, expression of truncated SHP2 reduced the interaction between endogenous, full-length SHP2 with the adapter protein, Grb2. To verify the role of SHP2 phosphatase function in human hematopoietic cell development, human cord blood CD34+ cells were transduced with a leukemia-associated phosphatase gain-of-function SHP2 mutant or with a phosphatase dead SHP2 mutant, which indicated that increased phosphatase function enhanced, while decreased SHP2 phosphatase function reduced, human cord blood-derived colonies. Collectively, these findings indicate that SHP2 phosphatase function regulates human hematopoietic cell development and imply that the phosphatase component of SHP2 may serve as a pharmacologic target in human leukemias bearing increased SHP2 phosphatase activity.",
author = "Hal Broxmeyer and Maryse Etienne-Julan and Akihiko Gotoh and Braun, {Stephen E.} and Li Lu and Scott Cooper and Feng, {Gen Sheng} and Li, {Xing Jun} and Rebecca Chan",
year = "2013",
month = "3",
day = "15",
doi = "10.1089/scd.2012.0478",
language = "English",
volume = "22",
pages = "998--1006",
journal = "Stem Cells and Development",
issn = "1547-3287",
publisher = "Mary Ann Liebert Inc.",
number = "6",

}

TY - JOUR

T1 - Hematopoietic colony formation from human growth factor-dependent TF1 cells and human cord blood myeloid progenitor cells depends on shp2 phosphatase function

AU - Broxmeyer, Hal

AU - Etienne-Julan, Maryse

AU - Gotoh, Akihiko

AU - Braun, Stephen E.

AU - Lu, Li

AU - Cooper, Scott

AU - Feng, Gen Sheng

AU - Li, Xing Jun

AU - Chan, Rebecca

PY - 2013/3/15

Y1 - 2013/3/15

N2 - The protein tyrosine phosphatase, SHP2, is widely expressed; however, previous studies demonstrated that hematopoietic cell development more stringently requires Shp2 expression compared to other tissues. Furthermore, somatic gain-of-function SHP2 mutants are commonly found in human myeloid leukemias. Given that pharmacologic inhibitors to SHP2 phosphatase activity are currently in development as putative antileukemic agents, we conducted a series of experiments examining the necessity of SHP2 phosphatase activity for human hematopoiesis. Anti-sense oligonucleotides to human SHP2 coding sequences reduced human cord blood- and human cell line, TF1-derived colony formation. Expression of truncated SHP2 bearing its Src homology 2 (SH2) domains, but lacking the phosphatase domain similarly reduced human cord blood- and TF1-derived colony formation. Mechanistically, expression of truncated SHP2 reduced the interaction between endogenous, full-length SHP2 with the adapter protein, Grb2. To verify the role of SHP2 phosphatase function in human hematopoietic cell development, human cord blood CD34+ cells were transduced with a leukemia-associated phosphatase gain-of-function SHP2 mutant or with a phosphatase dead SHP2 mutant, which indicated that increased phosphatase function enhanced, while decreased SHP2 phosphatase function reduced, human cord blood-derived colonies. Collectively, these findings indicate that SHP2 phosphatase function regulates human hematopoietic cell development and imply that the phosphatase component of SHP2 may serve as a pharmacologic target in human leukemias bearing increased SHP2 phosphatase activity.

AB - The protein tyrosine phosphatase, SHP2, is widely expressed; however, previous studies demonstrated that hematopoietic cell development more stringently requires Shp2 expression compared to other tissues. Furthermore, somatic gain-of-function SHP2 mutants are commonly found in human myeloid leukemias. Given that pharmacologic inhibitors to SHP2 phosphatase activity are currently in development as putative antileukemic agents, we conducted a series of experiments examining the necessity of SHP2 phosphatase activity for human hematopoiesis. Anti-sense oligonucleotides to human SHP2 coding sequences reduced human cord blood- and human cell line, TF1-derived colony formation. Expression of truncated SHP2 bearing its Src homology 2 (SH2) domains, but lacking the phosphatase domain similarly reduced human cord blood- and TF1-derived colony formation. Mechanistically, expression of truncated SHP2 reduced the interaction between endogenous, full-length SHP2 with the adapter protein, Grb2. To verify the role of SHP2 phosphatase function in human hematopoietic cell development, human cord blood CD34+ cells were transduced with a leukemia-associated phosphatase gain-of-function SHP2 mutant or with a phosphatase dead SHP2 mutant, which indicated that increased phosphatase function enhanced, while decreased SHP2 phosphatase function reduced, human cord blood-derived colonies. Collectively, these findings indicate that SHP2 phosphatase function regulates human hematopoietic cell development and imply that the phosphatase component of SHP2 may serve as a pharmacologic target in human leukemias bearing increased SHP2 phosphatase activity.

UR - http://www.scopus.com/inward/record.url?scp=84876216449&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876216449&partnerID=8YFLogxK

U2 - 10.1089/scd.2012.0478

DO - 10.1089/scd.2012.0478

M3 - Article

C2 - 23082805

AN - SCOPUS:84876216449

VL - 22

SP - 998

EP - 1006

JO - Stem Cells and Development

JF - Stem Cells and Development

SN - 1547-3287

IS - 6

ER -