CBL family E3 ubiquitin ligases control JAK2 ubiquitination and stability in hematopoietic stem cells and myeloid malignancies

Lv Kaosheng, Jing Jiang, Ryan Donaghy, Christopher R. Riling, Ying Cheng, Vemika Chandra, Krasimira Rozenova, Wei An, Bhopal C. Mohapatra, Benjamin T. Goetz, Vinodh Pillai, Xu Han, Emily A. Todd, Grace R. Jeschke, Wallace Y. Langdon, Suresh Kumar, Elizabeth O. Hexner, Hamid Band, Wei Tong

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Janus kinase 2 (JAK2) is a central kinase in hematopoietic stem/progenitor cells (HSPCs), and its uncontrolled activation is a prominent oncogenic driver of hematopoietic neoplasms. However, molecular mechanisms underlying the regulation of JAK2 have remained elusive. Here we report that the Casitas B-cell lymphoma (CBL) family E3 ubiquitin ligases down-regulate JAK2 stability and signaling via the adaptor protein LNK/SH2B3. We demonstrated that depletion of CBL/CBL-B or LNK abrogated JAK2 ubiquitination, extended JAK2 half-life, and enhanced JAK2 signaling and cell growth in human cell lines as well as primary murine HSPCs. Built on these findings, we showed that JAK inhibitor (JAKi) significantly reduced aberrant HSPCs and mitigated leukemia development in a mouse model of aggressive myeloid leukemia driven by loss of Cbl and Cbl-b. Importantly, primary human CBL mutated (CBLmut) leukemias exhibited increased JAK2 protein levels and signaling and were hypersensitive to JAKi. Loss-offunction mutations in CBL E3 ubiquitin ligases are found in a wide range of myeloid malignancies, which are diseases without effective treatment options. Hence, our studies reveal a novel signaling axis that regulates JAK2 in normal and malignant HSPCs and suggest new therapeutic strategies for treating CBLmut myeloid malignancies.

Original languageEnglish (US)
Pages (from-to)1007-1023
Number of pages17
JournalGenes and Development
Volume31
Issue number10
DOIs
StatePublished - May 15 2017

Fingerprint

Janus Kinase 2
Ubiquitin-Protein Ligases
Ubiquitination
B-Cell Lymphoma
Hematopoietic Stem Cells
Neoplasms
Leukemia
Myeloid Leukemia
Hematologic Neoplasms
Half-Life
Proteins
Phosphotransferases
Down-Regulation
Cell Line
Mutation

Keywords

  • Acute myeloid leukemia (AML)
  • Chronic myelomonocytic leukemia (CMML)
  • Hematopoietic stem cells (HSCs)
  • Janus kinase 2 (JAK2)
  • Juvenile myelomonocytic leukemia (JMML)
  • Signaling
  • Ubiquitin

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

CBL family E3 ubiquitin ligases control JAK2 ubiquitination and stability in hematopoietic stem cells and myeloid malignancies. / Kaosheng, Lv; Jiang, Jing; Donaghy, Ryan; Riling, Christopher R.; Cheng, Ying; Chandra, Vemika; Rozenova, Krasimira; An, Wei; Mohapatra, Bhopal C.; Goetz, Benjamin T.; Pillai, Vinodh; Han, Xu; Todd, Emily A.; Jeschke, Grace R.; Langdon, Wallace Y.; Kumar, Suresh; Hexner, Elizabeth O.; Band, Hamid; Tong, Wei.

In: Genes and Development, Vol. 31, No. 10, 15.05.2017, p. 1007-1023.

Research output: Contribution to journalArticle

Kaosheng, L, Jiang, J, Donaghy, R, Riling, CR, Cheng, Y, Chandra, V, Rozenova, K, An, W, Mohapatra, BC, Goetz, BT, Pillai, V, Han, X, Todd, EA, Jeschke, GR, Langdon, WY, Kumar, S, Hexner, EO, Band, H & Tong, W 2017, 'CBL family E3 ubiquitin ligases control JAK2 ubiquitination and stability in hematopoietic stem cells and myeloid malignancies', Genes and Development, vol. 31, no. 10, pp. 1007-1023. https://doi.org/10.1101/gad.297135.117
Kaosheng, Lv ; Jiang, Jing ; Donaghy, Ryan ; Riling, Christopher R. ; Cheng, Ying ; Chandra, Vemika ; Rozenova, Krasimira ; An, Wei ; Mohapatra, Bhopal C. ; Goetz, Benjamin T. ; Pillai, Vinodh ; Han, Xu ; Todd, Emily A. ; Jeschke, Grace R. ; Langdon, Wallace Y. ; Kumar, Suresh ; Hexner, Elizabeth O. ; Band, Hamid ; Tong, Wei. / CBL family E3 ubiquitin ligases control JAK2 ubiquitination and stability in hematopoietic stem cells and myeloid malignancies. In: Genes and Development. 2017 ; Vol. 31, No. 10. pp. 1007-1023.
@article{651af473bf104876acef32cdc9ec8c90,
title = "CBL family E3 ubiquitin ligases control JAK2 ubiquitination and stability in hematopoietic stem cells and myeloid malignancies",
abstract = "Janus kinase 2 (JAK2) is a central kinase in hematopoietic stem/progenitor cells (HSPCs), and its uncontrolled activation is a prominent oncogenic driver of hematopoietic neoplasms. However, molecular mechanisms underlying the regulation of JAK2 have remained elusive. Here we report that the Casitas B-cell lymphoma (CBL) family E3 ubiquitin ligases down-regulate JAK2 stability and signaling via the adaptor protein LNK/SH2B3. We demonstrated that depletion of CBL/CBL-B or LNK abrogated JAK2 ubiquitination, extended JAK2 half-life, and enhanced JAK2 signaling and cell growth in human cell lines as well as primary murine HSPCs. Built on these findings, we showed that JAK inhibitor (JAKi) significantly reduced aberrant HSPCs and mitigated leukemia development in a mouse model of aggressive myeloid leukemia driven by loss of Cbl and Cbl-b. Importantly, primary human CBL mutated (CBLmut) leukemias exhibited increased JAK2 protein levels and signaling and were hypersensitive to JAKi. Loss-offunction mutations in CBL E3 ubiquitin ligases are found in a wide range of myeloid malignancies, which are diseases without effective treatment options. Hence, our studies reveal a novel signaling axis that regulates JAK2 in normal and malignant HSPCs and suggest new therapeutic strategies for treating CBLmut myeloid malignancies.",
keywords = "Acute myeloid leukemia (AML), Chronic myelomonocytic leukemia (CMML), Hematopoietic stem cells (HSCs), Janus kinase 2 (JAK2), Juvenile myelomonocytic leukemia (JMML), Signaling, Ubiquitin",
author = "Lv Kaosheng and Jing Jiang and Ryan Donaghy and Riling, {Christopher R.} and Ying Cheng and Vemika Chandra and Krasimira Rozenova and Wei An and Mohapatra, {Bhopal C.} and Goetz, {Benjamin T.} and Vinodh Pillai and Xu Han and Todd, {Emily A.} and Jeschke, {Grace R.} and Langdon, {Wallace Y.} and Suresh Kumar and Hexner, {Elizabeth O.} and Hamid Band and Wei Tong",
year = "2017",
month = "5",
day = "15",
doi = "10.1101/gad.297135.117",
language = "English (US)",
volume = "31",
pages = "1007--1023",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "10",

}

TY - JOUR

T1 - CBL family E3 ubiquitin ligases control JAK2 ubiquitination and stability in hematopoietic stem cells and myeloid malignancies

AU - Kaosheng, Lv

AU - Jiang, Jing

AU - Donaghy, Ryan

AU - Riling, Christopher R.

AU - Cheng, Ying

AU - Chandra, Vemika

AU - Rozenova, Krasimira

AU - An, Wei

AU - Mohapatra, Bhopal C.

AU - Goetz, Benjamin T.

AU - Pillai, Vinodh

AU - Han, Xu

AU - Todd, Emily A.

AU - Jeschke, Grace R.

AU - Langdon, Wallace Y.

AU - Kumar, Suresh

AU - Hexner, Elizabeth O.

AU - Band, Hamid

AU - Tong, Wei

PY - 2017/5/15

Y1 - 2017/5/15

N2 - Janus kinase 2 (JAK2) is a central kinase in hematopoietic stem/progenitor cells (HSPCs), and its uncontrolled activation is a prominent oncogenic driver of hematopoietic neoplasms. However, molecular mechanisms underlying the regulation of JAK2 have remained elusive. Here we report that the Casitas B-cell lymphoma (CBL) family E3 ubiquitin ligases down-regulate JAK2 stability and signaling via the adaptor protein LNK/SH2B3. We demonstrated that depletion of CBL/CBL-B or LNK abrogated JAK2 ubiquitination, extended JAK2 half-life, and enhanced JAK2 signaling and cell growth in human cell lines as well as primary murine HSPCs. Built on these findings, we showed that JAK inhibitor (JAKi) significantly reduced aberrant HSPCs and mitigated leukemia development in a mouse model of aggressive myeloid leukemia driven by loss of Cbl and Cbl-b. Importantly, primary human CBL mutated (CBLmut) leukemias exhibited increased JAK2 protein levels and signaling and were hypersensitive to JAKi. Loss-offunction mutations in CBL E3 ubiquitin ligases are found in a wide range of myeloid malignancies, which are diseases without effective treatment options. Hence, our studies reveal a novel signaling axis that regulates JAK2 in normal and malignant HSPCs and suggest new therapeutic strategies for treating CBLmut myeloid malignancies.

AB - Janus kinase 2 (JAK2) is a central kinase in hematopoietic stem/progenitor cells (HSPCs), and its uncontrolled activation is a prominent oncogenic driver of hematopoietic neoplasms. However, molecular mechanisms underlying the regulation of JAK2 have remained elusive. Here we report that the Casitas B-cell lymphoma (CBL) family E3 ubiquitin ligases down-regulate JAK2 stability and signaling via the adaptor protein LNK/SH2B3. We demonstrated that depletion of CBL/CBL-B or LNK abrogated JAK2 ubiquitination, extended JAK2 half-life, and enhanced JAK2 signaling and cell growth in human cell lines as well as primary murine HSPCs. Built on these findings, we showed that JAK inhibitor (JAKi) significantly reduced aberrant HSPCs and mitigated leukemia development in a mouse model of aggressive myeloid leukemia driven by loss of Cbl and Cbl-b. Importantly, primary human CBL mutated (CBLmut) leukemias exhibited increased JAK2 protein levels and signaling and were hypersensitive to JAKi. Loss-offunction mutations in CBL E3 ubiquitin ligases are found in a wide range of myeloid malignancies, which are diseases without effective treatment options. Hence, our studies reveal a novel signaling axis that regulates JAK2 in normal and malignant HSPCs and suggest new therapeutic strategies for treating CBLmut myeloid malignancies.

KW - Acute myeloid leukemia (AML)

KW - Chronic myelomonocytic leukemia (CMML)

KW - Hematopoietic stem cells (HSCs)

KW - Janus kinase 2 (JAK2)

KW - Juvenile myelomonocytic leukemia (JMML)

KW - Signaling

KW - Ubiquitin

UR - http://www.scopus.com/inward/record.url?scp=85021204419&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021204419&partnerID=8YFLogxK

U2 - 10.1101/gad.297135.117

DO - 10.1101/gad.297135.117

M3 - Article

VL - 31

SP - 1007

EP - 1023

JO - Genes and Development

JF - Genes and Development

SN - 0890-9369

IS - 10

ER -