JAK2V617F allele burden ⩾50% is associated with response to ruxolitinib in persons with MPN-associated myelofibrosis and splenomegaly requiring therapy

Barosi, Giovanni; Klersy, Catherine; Villani, Laura; Bonetti, Elisa; Catarsi, Paolo; Poletto, Valentina; Campanelli, Rita; Impera, Stefana; Latagliata, Roberto; Viarengo, Gianluca; Carolei, Adriana; Massa, Margherita; Musso, Maurizio; Crescimanno, Alessandra; Gale, Robert Peter; Rosti, Vittorio

doi:10.1038/leu.2016.45

Cited by 49 publications

(39 citation statements)

References 12 publications

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“…We inhibited JAK1/2 (ruxolitinib) (29,30) in H292 cells. Following JAK1/2 inhibition, we analyzed the tyrosine phosphorylation of STAT3 (Y705), which is the downstream signaling target of JAK2 (31).…”

Section: Resultsmentioning

confidence: 99%

MUC16 Regulates TSPYL5 for Lung Cancer Cell Growth and Chemoresistance by Suppressing p53

Lakshmanan

Salfity

Seshacharyulu

et al. 2017

Clinical Cancer Research

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Purpose MUC16, a tumor biomarker and cell surface associated mucin, is overexpressed in various cancers; however, its role in lung cancer pathogenesis is unknown. Here, we have explored the mechanistic role of MUC16 in lung cancer. Experimental Design To identify the functional role of MUC16, stable knockdown was carried in lung cancer cells with two different shRNAs. Clinical significance of MUC16 was evaluated in lung cancer patient’s tissues using IHC. We have generated genetically engineered mouse model (KrasG12D; AdCre) to evaluate the preclinical significance of MUC16. Results MUC16 was overexpressed (P=0.03) in lung cancer as compared to normal. MUC16 knockdown (KD) in various lung cancer cell lines decreased the in vitro growth rate (P<0.05), migration (P<0.001), and in vivo tumor growth (P=0.007), while overexpression of MUC16-carboxyl terminal (MUC16-Cter) resulted in increased growth rate (P<0.001). Transcriptome analysis of MUC16 KD showed a downregulation (P=0.005) of TSPYL5 gene, which encodes for a testis-specific Y-like protein. Rescue studies via over-expression of MUC16-Cter in MUC16 KD cells showed activation of signaling proteins such as JAK2 (Y1007/1008), STAT3 (Y705) and glucocorticoid receptor (GR), which constitutes an important axis for the regulation of TSPYL5 for oncogenic process. Further, inhibition of STAT3 (Y705) led to decreased GR and TSPYL5 suggesting that MUC16 regulates TSPYL5 through the JAK2/STAT3/GR axis. Also, MUC16 overexpression induced cisplatin and gemcitabine resistance by down regulation of p53. Conclusions Our findings indicate a significant role of MUC16 in tumorigenesis and metastasis of lung cancer cells possibly via regulation of TSPYL5 through JAK2/STAT3/GR axis.

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Section: Resultsmentioning

confidence: 99%

MUC16 Regulates TSPYL5 for Lung Cancer Cell Growth and Chemoresistance by Suppressing p53

Lakshmanan

Salfity

Seshacharyulu

et al. 2017

Clinical Cancer Research

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“…This is not surprising (and it is good for patients) that ruxolitinib is efficacious irrespective of the underlying driver mutation. A JAK2V617F allele burden .50% predicts for better response to ruxolitinib, 5 although this observation requires confirmation. In the COMFORT-II study, 6 selected nondriver mutations included in the high-molecular-risk (HMR) category (ie, mutations in ASXL1, EZH2, SRSF2, IDH1, and IDH2) 7 had no impact on the likelihood of obtaining early splenic response and symptomatic improvement.…”

Section: Alessandro M Vannucchi and Paola Guglielmelli University Ofmentioning

confidence: 98%

“…4 These proteins are prominent targets of oncogenic mutations, as are the components of the nuclear transport system that modulate their effects. For example, nucleoporin fusion proteins have been found in leukemias with poor clinical outcomes, 5 whereas elevated XPO1 expression is associated with poor prognosis and drug resistance in several cancers. 6 XPO1 has long been considered a prominent target for therapeutic inhibition in cancers where its expression is abnormal, and also where it is normal, because in either situation blocking nucleocytoplasmic transport of tumor suppressors and apoptosis inhibitors has the potential to shift the cellular balance away from unregulated survival and proliferation.…”

Section: Sct -Mpl -Calr -Jak2 Vf >50%mentioning

confidence: 99%

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Vannucchi

Guglielmelli

2017

Blood

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“…Among JAK2-mutated patients with PMF, those with a lower JAK2 V617F allele burden may have a more myelodepletive than myeloproliferative phenotype and have been shown to have poorer survival [30,31]. Interestingly, a JAK2 V617F allele burden ≥ 50%, which has been associated with favorable survival [32], has also been reported to predict for greater responsiveness to ruxolitinib among patients with MF and splenomegaly requiring therapy [33].…”

Section: Biologymentioning

confidence: 99%

Mutational profiling in myelofibrosis: implications for management

Bose

Verstovšek

2019

Int J Hematol

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Mutational profiling, usually by targeted next-generation sequencing, is increasingly performed on patients with myeloproliferative neoplasm-associated myelofibrosis (MF), whether primary (PMF) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF). "Driver" mutations in JAK2, MPL and indels in CALR underlie the vast majority of cases of PMF and post-ET MF; the remainder (≈ 10%) lack identifiable driver mutations, but other clonal markers are usually detectable. Nearly all patients with post-PV MF carry activating JAK2 mutations. In both PMF and post-ET MF, type 1/-like CALR mutations confer a favorable prognosis. Since both type 1/-like and type 2/-like CALR mutations have essentially the same functional consequence, this is a subject of intense research. Additional, "non-driver" mutations, mostly affecting genes encoding epigenetic modifiers or spliceosome components, e.g., ASXL1, EZH2, TET2, DNMT3A, SRSF2 and U2AF1, are frequently found; some of these are associated with inferior survival and have been incorporated into prognostic models. Some mutations, e.g., IDH1/2, are relatively infrequent in chronic phase but are substantially more common in blast phase, and are now therapeutically targetable. While mutational information does not currently influence choice of drug therapy in chronic-phase MF, the presence of a "high molecular risk" genotype is now routinely taken into account for transplant decision-making.

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JAK2V617F allele burden ⩾50% is associated with response to ruxolitinib in persons with MPN-associated myelofibrosis and splenomegaly requiring therapy

Cited by 49 publications

References 12 publications

MUC16 Regulates TSPYL5 for Lung Cancer Cell Growth and Chemoresistance by Suppressing p53

MUC16 Regulates TSPYL5 for Lung Cancer Cell Growth and Chemoresistance by Suppressing p53

Traffic lights for ruxolitinib

Mutational profiling in myelofibrosis: implications for management

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