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.

Základní údaje

Originální název

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

Autoři

Vydání

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

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30205 Hematology

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 8.665

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14110/19:00108952

Organizační jednotka

Lékařská fakulta

Klíčová slova česky

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

Klíčová slova anglicky

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

Štítky

14110212, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 5. 5. 2020 09:13, Mgr. Tereza Miškechová

Anotace

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.

Citovat

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 a Steffen KOSCHMIEDER. JAK2V617F but not CALR mutations confer increased molecular responses to interferon-alpha via JAK1/STAT1 activation. Leukemia. London: Nature Publishung, 2019, roč. 33, č. 4, s. 995-1010. ISSN 0887-6924. Dostupné z: https://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 = {https://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 a Steffen KOSCHMIEDER. JAK2V617F but not CALR mutations confer increased molecular responses to interferon-alpha via JAK1/STAT1 activation. \textit{Leukemia}. London: Nature Publishung, 2019, roč.~33, č.~4, s.~995-1010. ISSN~0887-6924. Dostupné z: https://doi.org/10.1038/s41375-018-0295-6.

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