Yolk sac erythromyeloid progenitors expressing gain of function PTPN11 have functional features of JMML but are not sufficient to cause disease in mice

Stefan P. Tarnawsky, Momoko Yoshimoto, Lisa Deng, Rebecca Chan, Mervin Yoder

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: Accumulating evidence suggests the origin of juvenile myelomonocytic leukemia (JMML) is closely associated with fetal development. Nevertheless, the contribution of embryonic progenitors to JMML pathogenesis remains unexplored. We hypothesized that expression of JMML-initiating PTPN11 mutations in HSC-independent yolk sac erythromyeloid progenitors (YS EMPs) would result in a mouse model of pediatric myeloproliferative neoplasm (MPN). Results: E9.5 YS EMPs from VavCre+;PTPN11D61Y embryos demonstrated growth hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) and hyperactive RAS-ERK signaling. Mutant EMPs engrafted the spleens of neonatal recipients, but did not cause disease. To assess MPN development during unperturbed hematopoiesis we generated CSF1R-MCM+;PTPN11E76K;ROSAYFP mice in which oncogene expression was restricted to EMPs. Yellow fluorescent protein-positive progeny of mutant EMPs persisted in tissues one year after birth and demonstrated hyperactive RAS-ERK signaling. Nevertheless, these mice had normal survival and did not demonstrate features of MPN. Conclusions: YS EMPs expressing mutant PTPN11 demonstrate functional and molecular features of JMML but do not cause disease following transplantation nor following unperturbed development. Developmental Dynamics 246:1001–1014, 2017.

Original languageEnglish (US)
Pages (from-to)1001-1014
Number of pages14
JournalDevelopmental Dynamics
Volume246
Issue number12
DOIs
StatePublished - Dec 1 2017

Fingerprint

Juvenile Myelomonocytic Leukemia
Yolk Sac
Neoplasms
Hematopoiesis
Granulocyte-Macrophage Colony-Stimulating Factor
Fetal Development
Oncogenes
Hypersensitivity
Spleen
Embryonic Structures
Transplantation
Parturition
Pediatrics
Mutation
Growth
Proteins

Keywords

  • erythromyeloid progenitor
  • hematopoiesis
  • juvenile myelomonocytic leukemia
  • PTPN11
  • yolk sac

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Yolk sac erythromyeloid progenitors expressing gain of function PTPN11 have functional features of JMML but are not sufficient to cause disease in mice. / Tarnawsky, Stefan P.; Yoshimoto, Momoko; Deng, Lisa; Chan, Rebecca; Yoder, Mervin.

In: Developmental Dynamics, Vol. 246, No. 12, 01.12.2017, p. 1001-1014.

Research output: Contribution to journalArticle

@article{a6be1348b9484e98991175ca958218a3,
title = "Yolk sac erythromyeloid progenitors expressing gain of function PTPN11 have functional features of JMML but are not sufficient to cause disease in mice",
abstract = "Background: Accumulating evidence suggests the origin of juvenile myelomonocytic leukemia (JMML) is closely associated with fetal development. Nevertheless, the contribution of embryonic progenitors to JMML pathogenesis remains unexplored. We hypothesized that expression of JMML-initiating PTPN11 mutations in HSC-independent yolk sac erythromyeloid progenitors (YS EMPs) would result in a mouse model of pediatric myeloproliferative neoplasm (MPN). Results: E9.5 YS EMPs from VavCre+;PTPN11D61Y embryos demonstrated growth hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) and hyperactive RAS-ERK signaling. Mutant EMPs engrafted the spleens of neonatal recipients, but did not cause disease. To assess MPN development during unperturbed hematopoiesis we generated CSF1R-MCM+;PTPN11E76K;ROSAYFP mice in which oncogene expression was restricted to EMPs. Yellow fluorescent protein-positive progeny of mutant EMPs persisted in tissues one year after birth and demonstrated hyperactive RAS-ERK signaling. Nevertheless, these mice had normal survival and did not demonstrate features of MPN. Conclusions: YS EMPs expressing mutant PTPN11 demonstrate functional and molecular features of JMML but do not cause disease following transplantation nor following unperturbed development. Developmental Dynamics 246:1001–1014, 2017.",
keywords = "erythromyeloid progenitor, hematopoiesis, juvenile myelomonocytic leukemia, PTPN11, yolk sac",
author = "Tarnawsky, {Stefan P.} and Momoko Yoshimoto and Lisa Deng and Rebecca Chan and Mervin Yoder",
year = "2017",
month = "12",
day = "1",
doi = "10.1002/dvdy.24598",
language = "English (US)",
volume = "246",
pages = "1001--1014",
journal = "Developmental Dynamics",
issn = "1058-8388",
publisher = "Wiley-Liss Inc.",
number = "12",

}

TY - JOUR

T1 - Yolk sac erythromyeloid progenitors expressing gain of function PTPN11 have functional features of JMML but are not sufficient to cause disease in mice

AU - Tarnawsky, Stefan P.

AU - Yoshimoto, Momoko

AU - Deng, Lisa

AU - Chan, Rebecca

AU - Yoder, Mervin

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Background: Accumulating evidence suggests the origin of juvenile myelomonocytic leukemia (JMML) is closely associated with fetal development. Nevertheless, the contribution of embryonic progenitors to JMML pathogenesis remains unexplored. We hypothesized that expression of JMML-initiating PTPN11 mutations in HSC-independent yolk sac erythromyeloid progenitors (YS EMPs) would result in a mouse model of pediatric myeloproliferative neoplasm (MPN). Results: E9.5 YS EMPs from VavCre+;PTPN11D61Y embryos demonstrated growth hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) and hyperactive RAS-ERK signaling. Mutant EMPs engrafted the spleens of neonatal recipients, but did not cause disease. To assess MPN development during unperturbed hematopoiesis we generated CSF1R-MCM+;PTPN11E76K;ROSAYFP mice in which oncogene expression was restricted to EMPs. Yellow fluorescent protein-positive progeny of mutant EMPs persisted in tissues one year after birth and demonstrated hyperactive RAS-ERK signaling. Nevertheless, these mice had normal survival and did not demonstrate features of MPN. Conclusions: YS EMPs expressing mutant PTPN11 demonstrate functional and molecular features of JMML but do not cause disease following transplantation nor following unperturbed development. Developmental Dynamics 246:1001–1014, 2017.

AB - Background: Accumulating evidence suggests the origin of juvenile myelomonocytic leukemia (JMML) is closely associated with fetal development. Nevertheless, the contribution of embryonic progenitors to JMML pathogenesis remains unexplored. We hypothesized that expression of JMML-initiating PTPN11 mutations in HSC-independent yolk sac erythromyeloid progenitors (YS EMPs) would result in a mouse model of pediatric myeloproliferative neoplasm (MPN). Results: E9.5 YS EMPs from VavCre+;PTPN11D61Y embryos demonstrated growth hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) and hyperactive RAS-ERK signaling. Mutant EMPs engrafted the spleens of neonatal recipients, but did not cause disease. To assess MPN development during unperturbed hematopoiesis we generated CSF1R-MCM+;PTPN11E76K;ROSAYFP mice in which oncogene expression was restricted to EMPs. Yellow fluorescent protein-positive progeny of mutant EMPs persisted in tissues one year after birth and demonstrated hyperactive RAS-ERK signaling. Nevertheless, these mice had normal survival and did not demonstrate features of MPN. Conclusions: YS EMPs expressing mutant PTPN11 demonstrate functional and molecular features of JMML but do not cause disease following transplantation nor following unperturbed development. Developmental Dynamics 246:1001–1014, 2017.

KW - erythromyeloid progenitor

KW - hematopoiesis

KW - juvenile myelomonocytic leukemia

KW - PTPN11

KW - yolk sac

UR - http://www.scopus.com/inward/record.url?scp=85033983083&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85033983083&partnerID=8YFLogxK

U2 - 10.1002/dvdy.24598

DO - 10.1002/dvdy.24598

M3 - Article

C2 - 28975680

AN - SCOPUS:85033983083

VL - 246

SP - 1001

EP - 1014

JO - Developmental Dynamics

JF - Developmental Dynamics

SN - 1058-8388

IS - 12

ER -