The JAK2 V617F mutational status and allele burden may be related with the risk of venous thromboembolic events in patients with Philadelphia-negative myeloproliferative neoplasms.

INTRODUCTION: Patients with Philadelphia-negative myeloproliferative neoplasms (Ph(-) MPNs) are at increased risk of thromboembolic and hemorrhagic complications. The aim of the study was to determine the relationship between JAK2 V617F mutational status, JAK2 V617F allele burden and the risk of vascular complications occurrence. MATERIALS AND METHODS: Analysis was performed in a cohort of 186 patients diagnosed with polycythemia vera (53), essential thrombocythemia (114), primary myelofibrosis (11), and unclassified MPN (8). The risk of vascular complications development was analyzed in 126 JAK2 V617F-positive patients with respect to allele burden assessed with allele-specific 'real-time' quantitative polymerase chain reaction (AS RQ-PCR). RESULTS: Overall prevalence of any vascular complications was 44.6%. Arterial thrombosis occurred in 20.4%, venous thromboembolism (VTE) in 11.3%, bleeding episodes in 24.7% of patients. Individuals harboring JAK2 V617F mutation, regardless of MPN type, were at higher risk of VTE (OR=5.15, 95%CI: 1.16-22.90, P=0.024), mainly deep vein thrombosis (DVT). JAK2 allele burden higher than 20% identified patients with 7.4-fold increased risk of VTE (95%CI: 1.6-33.7, P=0.004), but not of arterial thrombosis, neither of bleeding complications, and remained the only significant VTE risk factor in multivariate logistic regression. High allele burdens (over 50%) were strikingly associated with proximal DVT cases, but not with distal DVT. CONCLUSIONS: The group of MPN patients with JAK2 V617F allele burden higher than 20% may benefit the most from vigilant monitoring and appropriate prophylaxis against vascular events. Inclusion of JAK2 V617F mutant allele burden in new risk stratifications seems to be justified and requires controlled prospective trials.

Frequency and molecular characteristics of calreticulin gene (CALR) mutations in patients with JAK2 -negative myeloproliferative neoplasms.

In 2013, Nangalia et al. and Klampfl et al. found a recurrent and abundant mutation in the calreticulin gene (CALR), mutually exclusive with JAK2 and MPL alterations. At present, the data concerning the new mutation, i.e. its prevalence, allele burden and clinical significance, are scarce. We report the incidence and molecular characteristics of CALR mutations in a group of 184 Polish patients with myeloproliferative neoplasms (MPNs). Clinical data analysis revealed significant differences between JAK2 V617F-mutated and CALR-mutated groups. In essential thrombocythemia patients, hemoglobin levels and leukocyte counts were significantly higher in JAK2-positive than in CALR-positive patients (p = 0.023 and p = 0.017, respectively), but the CALR-positive patients had significantly higher platelet counts (p = 0.022). Patients harboring CALR mutations were also younger at the time of diagnosis (p = 0.039). In primary myelofibrosis patients, the degree of anemia was less severe in those who were CALR exon 9 mutation-positive than in those who were JAK2 V617F-positive (p = 0.048).

Dasatinib treatment can overcome imatinib and nilotinib resistance in CML patient carrying F359I mutation of BCR-ABL oncogene.

Point mutations of bcr-abl tyrosine kinase are the most frequent causes of imatinib resistance in chronic myeloid leukaemia (CML) patients. In most CML cases with BCR-ABL mutations leading to imatinib resistance the second generation of tyrosine kinase inhibitors (TKI- e.g. nilotinib or dasatinib) may be effective. Here, we report a case of a CML patient who during imatinib treatment did not obtain clinical and cytogenetic response within 12 months of therapy. The sequencing of BCR-ABL kinase domains was performed and revealed the presence of a F359I point mutation (TTC-to-ATC nucleotide change leading to Phe-to-Ile amino acid substitution). After 1 month of nilotinib therapy a rapid progression of clinical symptoms was observed. In the presence of the F359I point mutation only dasatinib treatment overcame imatinib and nilotinib resistance.