TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms

Angela G. Fleischman, Karl J. Aichberger, Samuel B. Luty, Thomas G. Bumm, Curtis L. Petersen, Shirin Doratotaj, Kavin B. Vasudevan, Dorian H. LaTocha, Fei Yang, Richard Press, Marc Loriaux, Heike L. Pahl, Richard T. Silver, Anupriya Agarwal, Thomas O'Hare, Brian Druker, Grover C. Bagby, Michael W. Deininger

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Proinflammatory cytokines such as TNFα are elevated in patients with myeloproliferative neoplasms (MPN), but their contribution to disease pathogenesis is unknown. Here we reveal a central role for TNFα in promoting clonal dominance of JAK2V617F expressing cells in MPN. We show that JAK2V617F kinase regulates TNFα expression in cell lines and primary MPN cells and TNFα expression is correlated with JAK2V617F allele burden. In clonogenic assays, normal controls show reduced colony formation in the presence of TNFα while colony formation by JAK2V617F-positive progenitor cells is resistant or stimulated by exposure to TNFα. Ectopic JAK2V617F expression confers TNFα resistance to normal murine progenitor cells and overcomes inherent TNFα hypersensitivity of Fanconi anemia complementation group C deficient progenitors. Lastly, absence of TNFα limits clonal expansion and attenuates disease in a murine model of JAK2V617F-positive MPN. Altogether our data are consistent with a model where JAK2V617F promotes clonal selection by conferring TNFα resistance to a preneoplastic TNFα sensitive cell, while simultaneously generating a TNFα-rich environment. Mutations that confer resistance to environmental stem cell stressors are a recognized mechanism of clonal selection and leukemogenesis in bone marrow failure syndromes and our data suggest that this mechanism is also critical to clonal selection in MPN.

Original languageEnglish (US)
Pages (from-to)6392-6398
Number of pages7
JournalBlood
Volume118
Issue number24
DOIs
StatePublished - Dec 8 2011

Fingerprint

Cells
Stem cells
Stem Cells
Assays
Neoplasms
Bone
Phosphotransferases
Cytokines
Fanconi Anemia
Hypersensitivity
Alleles
Cell Line
Mutation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Fleischman, A. G., Aichberger, K. J., Luty, S. B., Bumm, T. G., Petersen, C. L., Doratotaj, S., ... Deininger, M. W. (2011). TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms. Blood, 118(24), 6392-6398. https://doi.org/10.1182/blood-2011-04-348144

TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms. / Fleischman, Angela G.; Aichberger, Karl J.; Luty, Samuel B.; Bumm, Thomas G.; Petersen, Curtis L.; Doratotaj, Shirin; Vasudevan, Kavin B.; LaTocha, Dorian H.; Yang, Fei; Press, Richard; Loriaux, Marc; Pahl, Heike L.; Silver, Richard T.; Agarwal, Anupriya; O'Hare, Thomas; Druker, Brian; Bagby, Grover C.; Deininger, Michael W.

In: Blood, Vol. 118, No. 24, 08.12.2011, p. 6392-6398.

Research output: Contribution to journalArticle

Fleischman, AG, Aichberger, KJ, Luty, SB, Bumm, TG, Petersen, CL, Doratotaj, S, Vasudevan, KB, LaTocha, DH, Yang, F, Press, R, Loriaux, M, Pahl, HL, Silver, RT, Agarwal, A, O'Hare, T, Druker, B, Bagby, GC & Deininger, MW 2011, 'TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms', Blood, vol. 118, no. 24, pp. 6392-6398. https://doi.org/10.1182/blood-2011-04-348144
Fleischman AG, Aichberger KJ, Luty SB, Bumm TG, Petersen CL, Doratotaj S et al. TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms. Blood. 2011 Dec 8;118(24):6392-6398. https://doi.org/10.1182/blood-2011-04-348144
Fleischman, Angela G. ; Aichberger, Karl J. ; Luty, Samuel B. ; Bumm, Thomas G. ; Petersen, Curtis L. ; Doratotaj, Shirin ; Vasudevan, Kavin B. ; LaTocha, Dorian H. ; Yang, Fei ; Press, Richard ; Loriaux, Marc ; Pahl, Heike L. ; Silver, Richard T. ; Agarwal, Anupriya ; O'Hare, Thomas ; Druker, Brian ; Bagby, Grover C. ; Deininger, Michael W. / TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms. In: Blood. 2011 ; Vol. 118, No. 24. pp. 6392-6398.
@article{6040d9bff9134fae89b6e4f2a7daec56,
title = "TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms",
abstract = "Proinflammatory cytokines such as TNFα are elevated in patients with myeloproliferative neoplasms (MPN), but their contribution to disease pathogenesis is unknown. Here we reveal a central role for TNFα in promoting clonal dominance of JAK2V617F expressing cells in MPN. We show that JAK2V617F kinase regulates TNFα expression in cell lines and primary MPN cells and TNFα expression is correlated with JAK2V617F allele burden. In clonogenic assays, normal controls show reduced colony formation in the presence of TNFα while colony formation by JAK2V617F-positive progenitor cells is resistant or stimulated by exposure to TNFα. Ectopic JAK2V617F expression confers TNFα resistance to normal murine progenitor cells and overcomes inherent TNFα hypersensitivity of Fanconi anemia complementation group C deficient progenitors. Lastly, absence of TNFα limits clonal expansion and attenuates disease in a murine model of JAK2V617F-positive MPN. Altogether our data are consistent with a model where JAK2V617F promotes clonal selection by conferring TNFα resistance to a preneoplastic TNFα sensitive cell, while simultaneously generating a TNFα-rich environment. Mutations that confer resistance to environmental stem cell stressors are a recognized mechanism of clonal selection and leukemogenesis in bone marrow failure syndromes and our data suggest that this mechanism is also critical to clonal selection in MPN.",
author = "Fleischman, {Angela G.} and Aichberger, {Karl J.} and Luty, {Samuel B.} and Bumm, {Thomas G.} and Petersen, {Curtis L.} and Shirin Doratotaj and Vasudevan, {Kavin B.} and LaTocha, {Dorian H.} and Fei Yang and Richard Press and Marc Loriaux and Pahl, {Heike L.} and Silver, {Richard T.} and Anupriya Agarwal and Thomas O'Hare and Brian Druker and Bagby, {Grover C.} and Deininger, {Michael W.}",
year = "2011",
month = "12",
day = "8",
doi = "10.1182/blood-2011-04-348144",
language = "English (US)",
volume = "118",
pages = "6392--6398",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "24",

}

TY - JOUR

T1 - TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms

AU - Fleischman, Angela G.

AU - Aichberger, Karl J.

AU - Luty, Samuel B.

AU - Bumm, Thomas G.

AU - Petersen, Curtis L.

AU - Doratotaj, Shirin

AU - Vasudevan, Kavin B.

AU - LaTocha, Dorian H.

AU - Yang, Fei

AU - Press, Richard

AU - Loriaux, Marc

AU - Pahl, Heike L.

AU - Silver, Richard T.

AU - Agarwal, Anupriya

AU - O'Hare, Thomas

AU - Druker, Brian

AU - Bagby, Grover C.

AU - Deininger, Michael W.

PY - 2011/12/8

Y1 - 2011/12/8

N2 - Proinflammatory cytokines such as TNFα are elevated in patients with myeloproliferative neoplasms (MPN), but their contribution to disease pathogenesis is unknown. Here we reveal a central role for TNFα in promoting clonal dominance of JAK2V617F expressing cells in MPN. We show that JAK2V617F kinase regulates TNFα expression in cell lines and primary MPN cells and TNFα expression is correlated with JAK2V617F allele burden. In clonogenic assays, normal controls show reduced colony formation in the presence of TNFα while colony formation by JAK2V617F-positive progenitor cells is resistant or stimulated by exposure to TNFα. Ectopic JAK2V617F expression confers TNFα resistance to normal murine progenitor cells and overcomes inherent TNFα hypersensitivity of Fanconi anemia complementation group C deficient progenitors. Lastly, absence of TNFα limits clonal expansion and attenuates disease in a murine model of JAK2V617F-positive MPN. Altogether our data are consistent with a model where JAK2V617F promotes clonal selection by conferring TNFα resistance to a preneoplastic TNFα sensitive cell, while simultaneously generating a TNFα-rich environment. Mutations that confer resistance to environmental stem cell stressors are a recognized mechanism of clonal selection and leukemogenesis in bone marrow failure syndromes and our data suggest that this mechanism is also critical to clonal selection in MPN.

AB - Proinflammatory cytokines such as TNFα are elevated in patients with myeloproliferative neoplasms (MPN), but their contribution to disease pathogenesis is unknown. Here we reveal a central role for TNFα in promoting clonal dominance of JAK2V617F expressing cells in MPN. We show that JAK2V617F kinase regulates TNFα expression in cell lines and primary MPN cells and TNFα expression is correlated with JAK2V617F allele burden. In clonogenic assays, normal controls show reduced colony formation in the presence of TNFα while colony formation by JAK2V617F-positive progenitor cells is resistant or stimulated by exposure to TNFα. Ectopic JAK2V617F expression confers TNFα resistance to normal murine progenitor cells and overcomes inherent TNFα hypersensitivity of Fanconi anemia complementation group C deficient progenitors. Lastly, absence of TNFα limits clonal expansion and attenuates disease in a murine model of JAK2V617F-positive MPN. Altogether our data are consistent with a model where JAK2V617F promotes clonal selection by conferring TNFα resistance to a preneoplastic TNFα sensitive cell, while simultaneously generating a TNFα-rich environment. Mutations that confer resistance to environmental stem cell stressors are a recognized mechanism of clonal selection and leukemogenesis in bone marrow failure syndromes and our data suggest that this mechanism is also critical to clonal selection in MPN.

UR - http://www.scopus.com/inward/record.url?scp=83455201579&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=83455201579&partnerID=8YFLogxK

U2 - 10.1182/blood-2011-04-348144

DO - 10.1182/blood-2011-04-348144

M3 - Article

C2 - 21860020

AN - SCOPUS:83455201579

VL - 118

SP - 6392

EP - 6398

JO - Blood

JF - Blood

SN - 0006-4971

IS - 24

ER -