Expert commentary: Despite significant reduction of splenomegaly and improvement of symptom burden and a signal for survival improvement, ruxolitinib does not lead to major reductions in JAK2V617F allele burden and bone marrow fibrosis.
One-hundred Mayo Clinic patients with high/intermediate-risk myelofibrosis (MF) received momelotinib (MMB; JAK1/2 inhibitor) between 2009 and 2010, as part of a phase 1/2 trial (NCT00935987); 73% harbored JAK2 mutations, 16% CALR, 7% MPL, 44% ASXL1, and 18% SRSF2.
Comparisons of JAK2 mutational status to clonality of hematopoiesis in essential thrombocythemia on the one hand, and to activation of transcription factors in myelofibrosis with myeloid metaplasia on the other hand, suggest that JAK2 mutation could be a second genetic event in a subset of patients.
Overall response rates (ORRs) in patients with JAK2 V617F-mutated PV, ET, and MF were 95%, 90.5%, and 9.1%, respectively, while patients with ET and MF without the JAK2V617F mutations had ORRs of 43.7% and 0%, respectively.
High levels of circulating CD34 cells, dacrocytes, clonal hematopoiesis, and JAK2 mutation differentiate myelofibrosis with myeloid metaplasia from secondary myelofibrosis associated with pulmonary hypertension.
Recently, novel calreticulin (CALR) mutations were discovered in Janus kinase 2 (JAK2) non-mutated myelofibrosis (PMF) and essential thrombocythemia (ET) cases, with a frequency of 60-80%.
The JAK2 c.1849G>T (p.V617F) mutation leads to constitutive activation of Janus kinase (JAK)2 and contributes to dysregulated JAK signaling in myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET).
Finally, we tested the combined effect of busulfan and veliparib on CD34<sup>+</sup> cells obtained from the bone marrow or peripheral blood of 5 patients with JAK2<sup>V617F</sup>-mutated and 2 patients with CALR-mutated MF.
The most prevalent mutation identified is a gain-of-function mutation in the Janus kinase (JAK) family, JAK2V617F, which has been identified in more than half of patients with myelofibrosis.
Interestingly, one of the patients with SM and the patient with CNL with JAK2V617F had a history of lymphoma, and this patient with SM also had associated myelofibrosis and CMML.
ABSTRACT: Background The BCR-ABL-negative myeloproliferative neoplasms, i.e., polycythemia vera, essential thrombocythemia (ET), and myelofibrosis (MF), are characterized by mutations in JAK2, CALR, or MPL.
These changes and the resultant clinical research are discussed in this article where we argue that discovery of the JAK2V617F mutation has signalled the much delayed change in therapeutic paradigm for myelofibrosis and possibly other MPNs from palliation and allowing us to move closer to, but not yet attain, a cure.
In bone marrow reconstitution models based on retroviral transduction, the phenotype induced by JAK2V617F is less severe and different from the rapid fatal myelofibrosis induced by TpoR W515L.
Higher JAK2(V617F) allele burden correlated with more advanced myelofibrosis, greater splenomegaly, and higher white blood cell count, but not with age, gender, hematocrit level, or frequency of phlebotomy prior to cytoreductive therapy.
Here, we show that treatment with the dual phosphoinositide-3-kinase (PI3K)/AKT and mTOR inhibitor BEZ235 attenuated PI3K/AKT and mTOR signaling, as well as induced cell-cycle growth arrest and apoptosis of the cultured human JAK2-V617F-expressing HEL92.1.7 (HEL), UKE1 cells, and primary CD34+ myelofibrosis (MF)-MPN cells.
Collectively, our studies demonstrate that occasional patients with CALR mutation-positive ET or MF carry other MPN-initiating genetic mutations (including JAK2 V617F), acquire "secondary mutations" before or after the CALR mutation, or evolve over time to being CALR mutation-homozygous.
ABSTRACT: Background The BCR-ABL-negative myeloproliferative neoplasms, i.e., polycythemia vera, essential thrombocythemia (ET), and myelofibrosis (MF), are characterized by mutations in JAK2, CALR, or MPL.