DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L) in 9% (4/45) of JAKV617F-negative MF.
The diagnosis of patients with mutant MPL alleles at the time of molecular testing was de novo MMM in 12 patients, ET in 4, post-ET MMM in 1, and MMM in blast crisis in 3.
Ruxolitinib, a selective JAK1/JAK2 inhibitor, is the current first line therapy for myelofibrosis (MF), which reduces symptomatology and splenomegaly, but does not clearly modify disease course.
"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.
Moreover, 4 therapeutic JAK2 inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) have either been approved or are in advanced clinical development for myelofibrosis.
Whether noncanonical and/or concomitant JAK2- and MPL-mutations exist in myelofibrosis (MF) regardless of phenotype-driver mutations is not yet elucidated.
To identify key features that may help distinguish these 2 entities, we retrospectively studied 21 cases diagnosed as "CMML" with JAK2V617F and bone marrow fibrosis that were identified from a cohort of 610 cases of CMML diagnosed in 2006 to 2016.
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.
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.
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.
The advances in molecular insights, especially the discovery of the Janus kinase 2 (JAK2) V617F mutation and its role in JAK-STAT pathway dysregulation, led to the development of the JAK inhibitor ruxolitinib, which currently represents the cornerstone of medical therapy in MF and hydroxyurea-resistant/intolerant PV.
Effect of CALR and JAK2 mutations on the clinical and hematological phenotypes of the disease in patients with myelofibrosis - long-term experience from a single center.
AML transformation occurred faster in SMF than in PMF and patients who transformed to AML were more SRSF2-mutated and less CALR-mutated at MF sampling.
A JAK2 variant in addition to JAK2V617F (n = 13) in myelofibrosis was associated with an increased cumulative risk of transformation into AML (P = .003).
With the advent of targeted therapies, such as the Janus kinase inhibitors, many patients have experienced substantial clinical benefits, including reduction in splenomegaly and symptoms and, in some instances, improvement or stabilization of bone marrow fibrosis and reduction of JAK2V617F allele burden.
Effect of CALR and JAK2 mutations on the clinical and hematological phenotypes of the disease in patients with myelofibrosis - long-term experience from a single center.
Treatment of patients with myelofibrosis with the type I JAK (Janus kinase) inhibitor ruxolitinib paradoxically induces JAK2 activation loop phosphorylation and is associated with a life-threatening cytokine-rebound syndrome if rapidly withdrawn.