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

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, Jiřı́; Ráčil, Zdeněk; Kubešová, Blanka; Knudsen, Trine Alma; Sørensen, Anders Lindholm; Holmström, Morten Orebo; Kjær, Lasse; Skov, Vibe; Larsen, Thomas Stauffer; Hasselbalch, Hans Carl; Chatain, Nicolas; Koschmieder, Steffen

doi:10.1038/s41375-018-0295-6

Cited by 46 publications

(49 citation statements)

References 59 publications

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“…In a retrospective analysis, while the percentage of complete hematological response was similar in the two groups, partial molecular remission (PMR) was significantly higher in JAK2 V617Fvs CALR-mutant patients (61 vs 20%), and nonresponse was higher in CALR-vs JAK2 V617F -mutant patients (70% vs 22%). 49 In line with these data, mean mutant allele burden decreased in JAK2 V617F -positive patients while it remained unchanged in CALR-positive patients. Koschmieder et al analyzed the mechanism for this discrepancy.…”

Section: Somatic Mutational Landscape Of Mpns and Immuno-oncology Tsupporting

confidence: 64%

Emerging translational science discoveries, clonal approaches, and treatment trends in chronic myeloproliferative neoplasms

Mughal

Pemmaraju

Radich

et al. 2019

Hematological Oncology

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The 60th American Society of Hematology (ASH) held in San Diego in December 2018 was followed by the 13th Post‐ASH chronic myeloproliferative neoplasms (MPNs) workshop on December 4 and 5, 2018. This closed annual workshop, first introduced in 2006 by Goldman and Mughal, was organized in collaboration with Alpine Oncology Foundation and allowed experts in preclinical and clinical research in the chronic MPNs to discuss the current scenario, including relevant presentations at ASH, and address pivotal open questions that impact translational research and clinical management. This review is based on the presentations and deliberations at this workshop, and rather than provide a resume of the proceedings, we have selected some of the important translational science and treatment issues that require clarity. We discuss the experimental and observational evidence to support the intimate interaction between aging, inflammation, and clonal evolution of MPNs, the clinical impact of the unfolding mutational landscape on the emerging targets and treatment of MPNs, new methods to detect clonal heterogeneity, the challenges in managing childhood and adolescent MPN, and reflect on the treatment of systemic mastocytosis (SM) following the licensing of midostaurin.

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Section: Somatic Mutational Landscape Of Mpns and Immuno-oncology Tsupporting

confidence: 64%

Emerging translational science discoveries, clonal approaches, and treatment trends in chronic myeloproliferative neoplasms

Mughal

Pemmaraju

Radich

et al. 2019

Hematological Oncology

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“…A decrease in CALR allele burden was previously described in 21/31 CALR‐ mutated ET patients with a median follow‐up of 12 years (Verger et al , ). A recent study showed a lower rate of molecular response to pegIFN in CALR ‐mutated compared to JAK2 V617F‐mutated MPN (20% of partial molecular response in CALR vs. 61% in JAK2 V617F) despite comparable haematological responses (Czech et al , ). In our study, the two patients with disease progression and decreased burden allele (Fig ) are treated with hydroxycarbamide and pegIFN respectively.…”

Section: Discussionmentioning

confidence: 99%

Sequential mutational evaluation of CALR ‐mutated myeloproliferative neoplasms with thrombocytosis reveals an association between CALR allele burden evolution and disease progression

et al. 2019

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Summary In myeloproliferative neoplasms (MPN), JAK2V617F allele burden measurement has an impact on prognosis that helps in patient monitoring. Less is known about its usefulness in CALR‐mutated cases. Additional mutations found by next‐generation sequencing have also shown an impact on prognosis that may drive therapeutic choices, especially in myelofibrosis, but few studies focused on CALR‐mutated patients. We performed a molecular evaluation combining next‐generation sequencing with a myeloid panel and CALR allele burden measurement at diagnosis and during follow‐up in a cohort of 45 patients with CALR‐mutated essential thrombocythaemia. The bone marrow histology was also blindly reviewed in order to apply the WHO2016 classification. The most frequently mutated gene was TET2 (11/21 mutations). CALR type 1‐like patients appear to have a more complex molecular landscape. We found an association between disease progression and CALR allele burden increase during follow‐up, independently of additional mutations and WHO2016‐reviewed diagnosis. Patients with disease progression at the time of follow‐up showed a significant increase in CALR allele burden (+16·7%, P = 0·005) whereas patients without disease progression had a stable allele burden (+3·7%, P = 0·194). This result argues for clinical interest in CALR allele burden monitoring.

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“…On the other hand, in another clinical study, peg-IFNα used at a higher dose did significantly reduce CALR allele burden, suggesting that CALR-positive patients are less sensitive to IFNα treatment compared to JAK2V617F patients [113]. A recent study suggested that the enhanced sensitivity of JAK2V1617F mutated cells to IFNα treatment was due to high expression and phosphorylated level of STAT1 [111]. Additionally, non-driver mutations in MPN also affect the response of the patients to IFNα treatment.…”

Section: Overview Of Mpn Therapymentioning

confidence: 97%

“…Of a particular note is the high molecular response rate of reducing allele burden in JAK2V617F positive patients treated with IFNα, suggesting that the treatment selectively targets JAK2 mutant clones. However, in CALR-positive patients, although the treatment of peg-IFNα achieves a comparable hematological response in comparison with JAK2V617F positive patients, the molecular remission was significantly compromised based on the data from two studies [111,112]. On the other hand, in another clinical study, peg-IFNα used at a higher dose did significantly reduce CALR allele burden, suggesting that CALR-positive patients are less sensitive to IFNα treatment compared to JAK2V617F patients [113].…”

Section: Overview Of Mpn Therapymentioning

confidence: 99%

Progress in elucidation of molecular pathophysiology of myeloproliferative neoplasms and its application to therapeutic decisions

Jia

Královics

2019

Int J Hematol

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Myeloproliferative neoplasms (MPNs) are hematological diseases that are driven by somatic mutations in hematopoietic stem and progenitor cells. These mutations include JAK2, CALR and MPL mutations as the main disease drivers, mutations driving clonal expansion, and mutations that contribute to progression of chronic MPNs to myelodysplasia and acute leukemia. JAK-STAT pathway has played a central role in the disease pathogenesis of MPNs. Mutant JAK2, CALR or MPL constitutively activates JAK-STAT pathway independent of the cytokine regulation. Symptomatic management is the primary goal of MPN therapy in ET and low-risk PV patients. JAK2 inhibitors and interferon-α are the established therapies in MF and high-risk PV patients.

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

Cited by 46 publications

References 59 publications

Emerging translational science discoveries, clonal approaches, and treatment trends in chronic myeloproliferative neoplasms

Emerging translational science discoveries, clonal approaches, and treatment trends in chronic myeloproliferative neoplasms

Sequential mutational evaluation of CALR ‐mutated myeloproliferative neoplasms with thrombocytosis reveals an association between CALR allele burden evolution and disease progression

Progress in elucidation of molecular pathophysiology of myeloproliferative neoplasms and its application to therapeutic decisions

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