JAK2V617F but not CALR mutations confer increased molecular
responses to interferon-alpha via JAK1/STAT1 activation

J 2019

JAK2V617F but not CALR mutations confer increased molecular responses to interferon-alpha via JAK1/STAT1 activation

CZECH, Julia; Sabrina CORDUA; Barbora WEINBERGEROVÁ; Julian BAUMEISTER; Assja CREPCIA et. al.

Basic information

Original name

JAK2V617F but not CALR mutations confer increased molecular responses to interferon-alpha via JAK1/STAT1 activation

Authors

CZECH, Julia (276 Germany); Sabrina CORDUA (208 Denmark); Barbora WEINBERGEROVÁ (203 Czech Republic, belonging to the institution); Julian BAUMEISTER (276 Germany); Assja CREPCIA (276 Germany); Lijuan HAN (276 Germany); Tiago MAIÉ (276 Germany); Ivan G. COSTA (276 Germany); Bernd DENECKE (276 Germany); Angela MAURER (276 Germany); Claudia SCHUBERT (276 Germany); Kristina FELDBERG (276 Germany); Deniz GEZER (276 Germany); Tim H. BRÜMMENDORF (276 Germany); Gerhard MÜLLER-NEWEN (276 Germany); Jiří MAYER (203 Czech Republic, belonging to the institution); Zdeněk RÁČIL (203 Czech Republic, belonging to the institution); Blanka KUBEŠOVÁ (203 Czech Republic, belonging to the institution); Trine KNUDSEN (208 Denmark); Anders L. SØRENSEN (208 Denmark); Morten HOLMSTRÖM (208 Denmark); Lasse KJÆR (208 Denmark); Vibe SKOV (208 Denmark); Thomas S. LARSEN (208 Denmark); Hans C. HASSELBALCH (208 Denmark); Nicolas CHATAIN (276 Germany) and Steffen KOSCHMIEDER (276 Germany, guarantor)

Edition

Leukemia, London, Nature Publishung, 2019, 0887-6924

Other information

Language

English

Type of outcome

Article in a journal

Field of Study

30205 Hematology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

is not subject to a state or trade secret

References:

URL

Impact factor

Impact factor: 8.665

RIV identification code

RIV/00216224:14110/19:00108952

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1038/s41375-018-0295-6

UT WoS

000463162400014

EID Scopus

2-s2.0-85057149022

Keywords (in Czech)

Ph negativní myeloproliferace; JAK2V617F; CALR; interferon alfa; molekulární odpověď

Keywords in English

Ph negative myeloproliferative disease; JAK2V617F; CALR; interferon alpha; molecular response

Abstract

V originále

Pegylated interferon-alpha (peg-IFNa) treatment induces molecular responses (MR) in patients with myeloproliferative neoplasms (MPNs), including partial MR (PMR) in 30-40% of patients. Here, we compared the efficacy of IFNa treatment in JAK2V617F-vs. calreticulin (CALR)-mutated cells and investigated the mechanisms of differential response. Retrospective analysis of MPN patients treated with peg-IFNa demonstrated that patients harboring the JAK2V617F mutation were more likely to achieve PMR than those with mutated CALR (p = 0.004), while there was no significant difference in hematological response. In vitro experiments confirmed an upregulation of IFN-stimulated genes in JAK2V617F-positive 32D cells as well as patient samples (peripheral blood mononuclear cells and CD34+ hematopoietic stem cells) compared to their CALR-mutated counterparts, and higher IFNa doses were needed to achieve the same IFNa response in CALR- as in JAK2V617F-mutant 32D cells. Additionally, Janus-activated kinase-1 (JAK1) and signal transducers and activators of transcription 1 (STAT1) showed constitutive phosphorylation in JAK2V617F-mutated but not CALR-mutated cells, indicating priming towards an IFNa response. Moreover, IFN-induced growth arrest was counteracted by selective JAK1 inhibition but enhanced by JAK2 inhibition. In conclusion, our data suggest that, clinically, higher doses of IFNa are needed in CALR-mutated vs. JAK2V617F-positive patients and we suggest a model of JAK2V617F-JAK1/ STAT1 crosstalk leading to a priming of JAK2V617F-positive cells to IFNa resulting in differential sensitivity.

Cite

CZECH, Julia; Sabrina CORDUA; Barbora WEINBERGEROVÁ; Julian BAUMEISTER; Assja CREPCIA; Lijuan HAN; Tiago MAIÉ; Ivan G. COSTA; Bernd DENECKE; Angela MAURER; Claudia SCHUBERT; Kristina FELDBERG; Deniz GEZER; Tim H. BRÜMMENDORF; Gerhard MÜLLER-NEWEN; Jiří MAYER; Zdeněk RÁČIL; Blanka KUBEŠOVÁ; Trine KNUDSEN; Anders L. SØRENSEN; Morten HOLMSTRÖM; Lasse KJÆR; Vibe SKOV; Thomas S. LARSEN; Hans C. HASSELBALCH; Nicolas CHATAIN and Steffen KOSCHMIEDER. JAK2V617F but not CALR mutations confer increased molecular responses to interferon-alpha via JAK1/STAT1 activation. Leukemia. London: Nature Publishung, 2019, vol. 33, No 4, p. 995-1010. ISSN 0887-6924. Available from: https://dx.doi.org/10.1038/s41375-018-0295-6.

@article{1476877,
   author = {Czech, Julia and Cordua, Sabrina and Weinbergerová, Barbora and Baumeister, Julian and Crepcia, Assja and Han, Lijuan and Maié, Tiago and Costa, Ivan G. and Denecke, Bernd and Maurer, Angela and Schubert, Claudia and Feldberg, Kristina and Gezer, Deniz and Brümmendorf, Tim H. and MüllerandNewen, Gerhard and Mayer, Jiří and Ráčil, Zdeněk and Kubešová, Blanka and Knudsen, Trine and Sørensen, Anders L. and Holmström, Morten and Kjær, Lasse and Skov, Vibe and Larsen, Thomas S. and Hasselbalch, Hans C. and Chatain, Nicolas and Koschmieder, Steffen},
   article_location = {London},
   article_number = {4},
   doi = {http://dx.doi.org/10.1038/s41375-018-0295-6},
   keywords = {Ph negative myeloproliferative disease; JAK2V617F; CALR; interferon alpha; molecular response},
   language = {eng},
   issn = {0887-6924},
   journal = {Leukemia},
   title = {JAK2V617F but not CALR mutations confer increased molecular responses to interferon-alpha via JAK1/STAT1 activation},
   url = {https://www.ncbi.nlm.nih.gov/pubmed/30470838},
   volume = {33},
   year = {2019}
}

TY  - JOUR
ID  - 1476877
AU  - Czech, Julia - Cordua, Sabrina - Weinbergerová, Barbora - Baumeister, Julian - Crepcia, Assja - Han, Lijuan - Maié, Tiago - Costa, Ivan G. - Denecke, Bernd - Maurer, Angela - Schubert, Claudia - Feldberg, Kristina - Gezer, Deniz - Brümmendorf, Tim H. - Müller-Newen, Gerhard - Mayer, Jiří - Ráčil, Zdeněk - Kubešová, Blanka - Knudsen, Trine - Sørensen, Anders L. - Holmström, Morten - Kjær, Lasse - Skov, Vibe - Larsen, Thomas S. - Hasselbalch, Hans C. - Chatain, Nicolas - Koschmieder, Steffen
PY  - 2019
TI  - JAK2V617F but not CALR mutations confer increased molecular responses to interferon-alpha via JAK1/STAT1 activation
JF  - Leukemia
VL  - 33
IS  - 4
SP  - 995-1010
EP  - 995-1010
PB  - Nature Publishung
SN  - 08876924
KW  - Ph negative myeloproliferative disease
KW  - JAK2V617F
KW  - CALR
KW  - interferon alpha
KW  - molecular response
UR  - https://www.ncbi.nlm.nih.gov/pubmed/30470838
L2  - https://www.ncbi.nlm.nih.gov/pubmed/30470838
N2  - Pegylated interferon-alpha (peg-IFNa) treatment induces molecular responses (MR) in patients with myeloproliferative neoplasms (MPNs), including partial MR (PMR) in 30-40% of patients. Here, we compared the efficacy of IFNa treatment in JAK2V617F-vs. calreticulin (CALR)-mutated cells and investigated the mechanisms of differential response. Retrospective analysis of MPN patients treated with peg-IFNa demonstrated that patients harboring the JAK2V617F mutation were more likely to achieve PMR than those with mutated CALR (p = 0.004), while there was no significant difference in hematological response. In vitro experiments confirmed an upregulation of IFN-stimulated genes in JAK2V617F-positive 32D cells as well as patient samples (peripheral blood mononuclear cells and CD34+ hematopoietic stem cells) compared to their CALR-mutated counterparts, and higher IFNa doses were needed to achieve the same IFNa response in CALR- as in JAK2V617F-mutant 32D cells. Additionally, Janus-activated kinase-1 (JAK1) and signal transducers and activators of transcription 1 (STAT1) showed constitutive phosphorylation in JAK2V617F-mutated but not CALR-mutated cells, indicating priming towards an IFNa response. Moreover, IFN-induced growth arrest was counteracted by selective JAK1 inhibition but enhanced by JAK2 inhibition. In conclusion, our data suggest that, clinically, higher doses of IFNa are needed in CALR-mutated vs. JAK2V617F-positive patients and we suggest a model of JAK2V617F-JAK1/ STAT1 crosstalk leading to a priming of JAK2V617F-positive cells to IFNa resulting in differential sensitivity.
ER  -

CZECH, Julia; Sabrina CORDUA; Barbora WEINBERGEROVÁ; Julian BAUMEISTER; Assja CREPCIA; Lijuan HAN; Tiago MAIÉ; Ivan G. COSTA; Bernd DENECKE; Angela MAURER; Claudia SCHUBERT; Kristina FELDBERG; Deniz GEZER; Tim H. BRÜMMENDORF; Gerhard MÜLLER-NEWEN; Jiří MAYER; Zdeněk RÁČIL; Blanka KUBEŠOVÁ; Trine KNUDSEN; Anders L. SØRENSEN; Morten HOLMSTRÖM; Lasse KJÆR; Vibe SKOV; Thomas S. LARSEN; Hans C. HASSELBALCH; Nicolas CHATAIN and Steffen KOSCHMIEDER. JAK2V617F but not CALR mutations confer increased molecular responses to interferon-alpha via JAK1/STAT1 activation. \textit{Leukemia}. London: Nature Publishung, 2019, vol.~33, No~4, p.~995-1010. ISSN~0887-6924. Available from: https://dx.doi.org/10.1038/s41375-018-0295-6.

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