Apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells

Britta Will, Tanya Siddiqi, Meritxell Alberich Jordà, Takeshi Shimamura, Katarina Luptakova, Philipp B. Staber, Daniel B. Costa, Ulrich G. Steidl, Daniel G. Tenen, Susumu Kobayashi

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

The activating mutation JAK2 V617F plays a central role in the pathogenesis of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Inhibition of JAK2 activity leads to growth inhibition and apoptosis in cells with mutated JAK2. However, the proapoptotic proteins involved in JAK2 inhibition-induced apoptosis remain unclear. In this study, we show that JAK2 inhibition-induced apoptosis correlated with upregulation of the nonphosphorylated form of the BH3-only protein Bim in hematopoietic cell lines bearing JAK2 mutations. Knockdown of Bim dramatically inhibited apoptosis induced by JAK2 inhibition, which was reversed by the BH3 mimetic agent ABT-737. In addition, ABT-737 enhanced the apoptosis induced by JAK2 inhibition in JAK2 V617F+ HEL and SET-2 cells. The combination of JAK inhibitor I and ABT-737 reduced the number of erythroid colonies derived from CD34+ cells isolated from JAK2 V617F+ polycythemia vera patients more efficiently than either drug alone. These data suggest that Bim is a key effector molecule in JAK2 inhibition-induced apoptosis and that targeting this apoptotic pathway could be a novel therapeutic strategy for patients with activating JAK2 mutations.

Original languageEnglish (US)
Pages (from-to)2901-2909
Number of pages9
JournalBlood
Volume115
Issue number14
DOIs
StatePublished - Apr 8 2010

Fingerprint

Erythroid Cells
Apoptosis
Polycythemia Vera
Mutation
Bearings (structural)
Essential Thrombocythemia
Primary Myelofibrosis
ABT-737
Proteins
Up-Regulation
Cells
Cell Line
Molecules
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells. / Will, Britta; Siddiqi, Tanya; Jordà, Meritxell Alberich; Shimamura, Takeshi; Luptakova, Katarina; Staber, Philipp B.; Costa, Daniel B.; Steidl, Ulrich G.; Tenen, Daniel G.; Kobayashi, Susumu.

In: Blood, Vol. 115, No. 14, 08.04.2010, p. 2901-2909.

Research output: Contribution to journalArticle

Will, B, Siddiqi, T, Jordà, MA, Shimamura, T, Luptakova, K, Staber, PB, Costa, DB, Steidl, UG, Tenen, DG & Kobayashi, S 2010, 'Apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells', Blood, vol. 115, no. 14, pp. 2901-2909. https://doi.org/10.1182/blood-2009-03-209544
Will, Britta ; Siddiqi, Tanya ; Jordà, Meritxell Alberich ; Shimamura, Takeshi ; Luptakova, Katarina ; Staber, Philipp B. ; Costa, Daniel B. ; Steidl, Ulrich G. ; Tenen, Daniel G. ; Kobayashi, Susumu. / Apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells. In: Blood. 2010 ; Vol. 115, No. 14. pp. 2901-2909.
@article{f294a201baa74846908579f7dbef83f6,
title = "Apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells",
abstract = "The activating mutation JAK2 V617F plays a central role in the pathogenesis of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Inhibition of JAK2 activity leads to growth inhibition and apoptosis in cells with mutated JAK2. However, the proapoptotic proteins involved in JAK2 inhibition-induced apoptosis remain unclear. In this study, we show that JAK2 inhibition-induced apoptosis correlated with upregulation of the nonphosphorylated form of the BH3-only protein Bim in hematopoietic cell lines bearing JAK2 mutations. Knockdown of Bim dramatically inhibited apoptosis induced by JAK2 inhibition, which was reversed by the BH3 mimetic agent ABT-737. In addition, ABT-737 enhanced the apoptosis induced by JAK2 inhibition in JAK2 V617F+ HEL and SET-2 cells. The combination of JAK inhibitor I and ABT-737 reduced the number of erythroid colonies derived from CD34+ cells isolated from JAK2 V617F+ polycythemia vera patients more efficiently than either drug alone. These data suggest that Bim is a key effector molecule in JAK2 inhibition-induced apoptosis and that targeting this apoptotic pathway could be a novel therapeutic strategy for patients with activating JAK2 mutations.",
author = "Britta Will and Tanya Siddiqi and Jord{\`a}, {Meritxell Alberich} and Takeshi Shimamura and Katarina Luptakova and Staber, {Philipp B.} and Costa, {Daniel B.} and Steidl, {Ulrich G.} and Tenen, {Daniel G.} and Susumu Kobayashi",
year = "2010",
month = "4",
day = "8",
doi = "10.1182/blood-2009-03-209544",
language = "English (US)",
volume = "115",
pages = "2901--2909",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "14",

}

TY - JOUR

T1 - Apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells

AU - Will, Britta

AU - Siddiqi, Tanya

AU - Jordà, Meritxell Alberich

AU - Shimamura, Takeshi

AU - Luptakova, Katarina

AU - Staber, Philipp B.

AU - Costa, Daniel B.

AU - Steidl, Ulrich G.

AU - Tenen, Daniel G.

AU - Kobayashi, Susumu

PY - 2010/4/8

Y1 - 2010/4/8

N2 - The activating mutation JAK2 V617F plays a central role in the pathogenesis of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Inhibition of JAK2 activity leads to growth inhibition and apoptosis in cells with mutated JAK2. However, the proapoptotic proteins involved in JAK2 inhibition-induced apoptosis remain unclear. In this study, we show that JAK2 inhibition-induced apoptosis correlated with upregulation of the nonphosphorylated form of the BH3-only protein Bim in hematopoietic cell lines bearing JAK2 mutations. Knockdown of Bim dramatically inhibited apoptosis induced by JAK2 inhibition, which was reversed by the BH3 mimetic agent ABT-737. In addition, ABT-737 enhanced the apoptosis induced by JAK2 inhibition in JAK2 V617F+ HEL and SET-2 cells. The combination of JAK inhibitor I and ABT-737 reduced the number of erythroid colonies derived from CD34+ cells isolated from JAK2 V617F+ polycythemia vera patients more efficiently than either drug alone. These data suggest that Bim is a key effector molecule in JAK2 inhibition-induced apoptosis and that targeting this apoptotic pathway could be a novel therapeutic strategy for patients with activating JAK2 mutations.

AB - The activating mutation JAK2 V617F plays a central role in the pathogenesis of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Inhibition of JAK2 activity leads to growth inhibition and apoptosis in cells with mutated JAK2. However, the proapoptotic proteins involved in JAK2 inhibition-induced apoptosis remain unclear. In this study, we show that JAK2 inhibition-induced apoptosis correlated with upregulation of the nonphosphorylated form of the BH3-only protein Bim in hematopoietic cell lines bearing JAK2 mutations. Knockdown of Bim dramatically inhibited apoptosis induced by JAK2 inhibition, which was reversed by the BH3 mimetic agent ABT-737. In addition, ABT-737 enhanced the apoptosis induced by JAK2 inhibition in JAK2 V617F+ HEL and SET-2 cells. The combination of JAK inhibitor I and ABT-737 reduced the number of erythroid colonies derived from CD34+ cells isolated from JAK2 V617F+ polycythemia vera patients more efficiently than either drug alone. These data suggest that Bim is a key effector molecule in JAK2 inhibition-induced apoptosis and that targeting this apoptotic pathway could be a novel therapeutic strategy for patients with activating JAK2 mutations.

UR - http://www.scopus.com/inward/record.url?scp=77951041842&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951041842&partnerID=8YFLogxK

U2 - 10.1182/blood-2009-03-209544

DO - 10.1182/blood-2009-03-209544

M3 - Article

C2 - 20160166

AN - SCOPUS:77951041842

VL - 115

SP - 2901

EP - 2909

JO - Blood

JF - Blood

SN - 0006-4971

IS - 14

ER -