Abstract

Cbl and Cbl-b are tyrosine kinase-directed RING finger type ubiquitin ligases (E3s) that negatively regulate cellular activation pathways. E3 activity-disrupting human Cbl mutations are associated with myeloproliferative disorders (MPD) that are reproduced in mice with Cbl RING finger mutant knock-in or hematopoietic Cbl and Cbl-b double knockout. However, the role of Cbl proteins in hematopoietic stem cell (HSC) homeostasis, especially in the context of MPD is unclear. Here we demonstrate that HSC expansion and MPD development upon combined Cbl and Cbl-b deletion are dependent on HSCs. Cell cycle analysis demonstrated that DKO HSCs exhibit reduced quiescence associated with compromised reconstitution ability and propensity to undergo exhaustion. We show that sustained c-Kit and FLT3 signaling in DKO HSCs promotes loss of colony-forming potential, and c-Kit or FLT3 inhibition in vitro protects HSCs from exhaustion. In vivo, treatment with 5-fluorouracil hastens DKO HSC exhaustion and protects mice from death due to MPD. Our data reveal a novel and leukemia therapy-relevant role of Cbl and Cbl-b in the maintenance of HSC quiescence and protection against exhaustion, through negative regulation of tyrosine kinase-coupled receptor signaling.

Original languageEnglish (US)
Pages (from-to)10498-10509
Number of pages12
JournalOncotarget
Volume6
Issue number12
DOIs
StatePublished - Jan 1 2015

Fingerprint

Myeloproliferative Disorders
Ligases
Hematopoietic Stem Cells
Ubiquitin
Drug Therapy
Cytoprotection
Receptor Protein-Tyrosine Kinases
Human Activities
Fluorouracil
Protein-Tyrosine Kinases
Cell Cycle
Leukemia
Homeostasis
Maintenance
Mutation
Therapeutics
Proteins

Keywords

  • Cbl
  • HSC
  • Quiescence
  • Tyrosine kinase
  • Ubiquitin ligase

ASJC Scopus subject areas

  • Oncology

Cite this

Loss of Cbl and Cbl-b ubiquitin ligases abrogates hematopoietic stem cell quiescence and sensitizes leukemic disease to chemotherapy. / An, Wei; Nadeau, Scott A.; Mohapatra, Bhopal C.; Feng, Dan; Zutshi, Neha; Storck, Matthew D.; Arya, Priyanka; Talmadge, James E; Meza, Jane L; Band, Vimla; Band, Hamid.

In: Oncotarget, Vol. 6, No. 12, 01.01.2015, p. 10498-10509.

Research output: Contribution to journalArticle

An, Wei ; Nadeau, Scott A. ; Mohapatra, Bhopal C. ; Feng, Dan ; Zutshi, Neha ; Storck, Matthew D. ; Arya, Priyanka ; Talmadge, James E ; Meza, Jane L ; Band, Vimla ; Band, Hamid. / Loss of Cbl and Cbl-b ubiquitin ligases abrogates hematopoietic stem cell quiescence and sensitizes leukemic disease to chemotherapy. In: Oncotarget. 2015 ; Vol. 6, No. 12. pp. 10498-10509.
@article{1a9c4d7a89fb4d8d98b834fab60ce58f,
title = "Loss of Cbl and Cbl-b ubiquitin ligases abrogates hematopoietic stem cell quiescence and sensitizes leukemic disease to chemotherapy",
abstract = "Cbl and Cbl-b are tyrosine kinase-directed RING finger type ubiquitin ligases (E3s) that negatively regulate cellular activation pathways. E3 activity-disrupting human Cbl mutations are associated with myeloproliferative disorders (MPD) that are reproduced in mice with Cbl RING finger mutant knock-in or hematopoietic Cbl and Cbl-b double knockout. However, the role of Cbl proteins in hematopoietic stem cell (HSC) homeostasis, especially in the context of MPD is unclear. Here we demonstrate that HSC expansion and MPD development upon combined Cbl and Cbl-b deletion are dependent on HSCs. Cell cycle analysis demonstrated that DKO HSCs exhibit reduced quiescence associated with compromised reconstitution ability and propensity to undergo exhaustion. We show that sustained c-Kit and FLT3 signaling in DKO HSCs promotes loss of colony-forming potential, and c-Kit or FLT3 inhibition in vitro protects HSCs from exhaustion. In vivo, treatment with 5-fluorouracil hastens DKO HSC exhaustion and protects mice from death due to MPD. Our data reveal a novel and leukemia therapy-relevant role of Cbl and Cbl-b in the maintenance of HSC quiescence and protection against exhaustion, through negative regulation of tyrosine kinase-coupled receptor signaling.",
keywords = "Cbl, HSC, Quiescence, Tyrosine kinase, Ubiquitin ligase",
author = "Wei An and Nadeau, {Scott A.} and Mohapatra, {Bhopal C.} and Dan Feng and Neha Zutshi and Storck, {Matthew D.} and Priyanka Arya and Talmadge, {James E} and Meza, {Jane L} and Vimla Band and Hamid Band",
year = "2015",
month = "1",
day = "1",
doi = "10.18632/oncotarget.3403",
language = "English (US)",
volume = "6",
pages = "10498--10509",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "12",

}

TY - JOUR

T1 - Loss of Cbl and Cbl-b ubiquitin ligases abrogates hematopoietic stem cell quiescence and sensitizes leukemic disease to chemotherapy

AU - An, Wei

AU - Nadeau, Scott A.

AU - Mohapatra, Bhopal C.

AU - Feng, Dan

AU - Zutshi, Neha

AU - Storck, Matthew D.

AU - Arya, Priyanka

AU - Talmadge, James E

AU - Meza, Jane L

AU - Band, Vimla

AU - Band, Hamid

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Cbl and Cbl-b are tyrosine kinase-directed RING finger type ubiquitin ligases (E3s) that negatively regulate cellular activation pathways. E3 activity-disrupting human Cbl mutations are associated with myeloproliferative disorders (MPD) that are reproduced in mice with Cbl RING finger mutant knock-in or hematopoietic Cbl and Cbl-b double knockout. However, the role of Cbl proteins in hematopoietic stem cell (HSC) homeostasis, especially in the context of MPD is unclear. Here we demonstrate that HSC expansion and MPD development upon combined Cbl and Cbl-b deletion are dependent on HSCs. Cell cycle analysis demonstrated that DKO HSCs exhibit reduced quiescence associated with compromised reconstitution ability and propensity to undergo exhaustion. We show that sustained c-Kit and FLT3 signaling in DKO HSCs promotes loss of colony-forming potential, and c-Kit or FLT3 inhibition in vitro protects HSCs from exhaustion. In vivo, treatment with 5-fluorouracil hastens DKO HSC exhaustion and protects mice from death due to MPD. Our data reveal a novel and leukemia therapy-relevant role of Cbl and Cbl-b in the maintenance of HSC quiescence and protection against exhaustion, through negative regulation of tyrosine kinase-coupled receptor signaling.

AB - Cbl and Cbl-b are tyrosine kinase-directed RING finger type ubiquitin ligases (E3s) that negatively regulate cellular activation pathways. E3 activity-disrupting human Cbl mutations are associated with myeloproliferative disorders (MPD) that are reproduced in mice with Cbl RING finger mutant knock-in or hematopoietic Cbl and Cbl-b double knockout. However, the role of Cbl proteins in hematopoietic stem cell (HSC) homeostasis, especially in the context of MPD is unclear. Here we demonstrate that HSC expansion and MPD development upon combined Cbl and Cbl-b deletion are dependent on HSCs. Cell cycle analysis demonstrated that DKO HSCs exhibit reduced quiescence associated with compromised reconstitution ability and propensity to undergo exhaustion. We show that sustained c-Kit and FLT3 signaling in DKO HSCs promotes loss of colony-forming potential, and c-Kit or FLT3 inhibition in vitro protects HSCs from exhaustion. In vivo, treatment with 5-fluorouracil hastens DKO HSC exhaustion and protects mice from death due to MPD. Our data reveal a novel and leukemia therapy-relevant role of Cbl and Cbl-b in the maintenance of HSC quiescence and protection against exhaustion, through negative regulation of tyrosine kinase-coupled receptor signaling.

KW - Cbl

KW - HSC

KW - Quiescence

KW - Tyrosine kinase

KW - Ubiquitin ligase

UR - http://www.scopus.com/inward/record.url?scp=84929590464&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84929590464&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.3403

DO - 10.18632/oncotarget.3403

M3 - Article

VL - 6

SP - 10498

EP - 10509

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 12

ER -