MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients

Abstract

Recently, a gain-of-function MPL mutation, MPLW515L, was described in patients with JAK2V617F-negative myelofibrosis with myeloid metaplasia (MMM). To gain more information on mutational frequency, disease specificity, and clinical correlates, genomic DNA from 1182 patients with myeloproliferative and other myeloid disorders and 64 healthy controls was screened for MPL515 mutations, regardless of JAK2V617F mutational status: 290 with MMM, 242 with polycythemia vera, 318 with essential thrombocythemia (ET), 88 with myelodysplastic syndrome, 118 with chronic myelomonocytic leukemia, and 126 with acute myeloid leukemia (AML). MPL515 mutations, either MPLW515L (n ‫؍‬ 17) or a previously undescribed MPLW515K (n ‫؍‬ 5), were detected in 20 patients. 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. Six patients carried the MPLW515L and JAK2V617F alleles concurrently. We conclude that MPLW515L or MPLW515K mutations are present in patients with MMM or ET at a frequency of approximately 5% and 1%, respectively, but are not observed in patients with polycythemia vera (PV) or other myeloid disorders. Furthermore, MPL mutations may occur concurrently with the JAK2V617F mutation, suggesting that these alleles may have functional complementation in myeloproliferative disease.

The role of Janus Kinase 2 V617F mutation in extramedullary hematopoiesis of the spleen in neoplastic myeloid disorders

“…19 It would be of great interest to further study our cohort of cases once assays using paraffin-embedded tissues become commercially available to detect other mutations associated with CMPD or acute leukemia, such as MPL-W515L, MPL-W515K, JAK2-L611S, JAK2-K607N and JAK2-T875N. [31][32][33][34][35][36] The finding of increased Bcl-xL expression in megakaryocytes of JAK2 V617F -positive spleen specimens suggests that the JAK2 V617F mutation may induce myeloproliferation via the STAT5/Bcl-xL pathway, at least partially, in splenic EMH. In support, sustained high levels of Bcl-xL were recently demonstrated to promote erythropoietin independent colony formation in vitro.…”

One Thousand Patients With Primary Myelofibrosis: The Mayo Clinic Experience

“…MPL and JAK2 mutation analyses were performed according to previously published methods. [26][27][28][29] IDH1 and IDH2 mutations were analyzed by direct sequencing and/or high-resolution melting assay. 30 Unfavorable karyotype designation 31 and International Prognostic Scoring System (IPSS), 32 DIPSS, 33 and DIPSSplus 21 21 Leukemic transformation risk was considered high in the presence of unfavorable karyotype or platelet count less than 100 ϫ 10 9 /L or low in the absence of both of these risk factors.…”

Prodromal myeloproliferative neoplasms: The 2008 WHO classification

“…In this regard, diagnostic criteria for the classical Philadelphia chromosome-negative (Ph 12 ) MPN as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), have been substantially changed by inclusion of the JAK2V617F mutation status and similar activating mutations [3,4]. As a consequence clinicians are becoming more and more aware that a positive expression of these markers including Exon 12 and MPLW 515L/K mutations [3,4,8,[11][12][13][14][15][16][17] may discriminate reactive from neoplastic conditions even in initial-early stage MPN. On the other hand, because JAK2V617F mutation was reported in virtually all patients with PV and up to 50% of cases with ET and PMF, its presence alone does not help in subclassification of MPN nor does a negative finding definitively exclude a MPN [3,4].…”