Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms.

Recent evidence has demonstrated that acquired uniparental disomy (aUPD) is a novel mechanism by which pathogenetic mutations in cancer may be reduced to homozygosity. To help identify novel mutations in myeloproliferative neoplasms (MPNs), we performed a genome-wide single nucleotide polymorphism (SNP) screen to identify aUPD in 58 patients with atypical chronic myeloid leukemia (aCML; n = 30), JAK2 mutation-negative myelofibrosis (MF; n = 18), or JAK2 mutation-negative polycythemia vera (PV; n = 10). Stretches of homozygous, copy neutral SNP calls greater than 20Mb were seen in 10 (33%) aCML and 1 (6%) MF, but were absent in PV. In total, 7 different chromosomes were involved with 7q and 11q each affected in 10% of aCML cases. CBL mutations were identified in all 3 cases with 11q aUPD and analysis of 574 additional MPNs revealed a total of 27 CBL variants in 26 patients with aCML, myelofibrosis or chronic myelomonocytic leukemia. Most variants were missense substitutions in the RING or linker domains that abrogated CBL ubiquitin ligase activity and conferred a proliferative advantage to 32D cells overexpressing FLT3. We conclude that acquired, transforming CBL mutations are a novel and widespread pathogenetic abnormality in morphologically related, clinically aggressive MPNs.

Is JAK2 V617F mutation more than a diagnostic index? A meta-analysis of clinical outcomes in essential thrombocythemia.

A systematic review and meta-analysis was carried out to compare the frequency of clinically significant outcomes between JAK2 V617F positive and wild type patients with essential thrombocythemia (ET). JAK2 V617F positivity in patients with ET was associated with a clear increase in the odds of thrombosis [OR=1.83 (95% CI, 1.32-2.53), p<0.0001], and much higher odds of transformation to polycythemia vera [OR=7.67 (95% CI, 2.04-28.87), p=0.0009]. The mean difference of the white blood cell count between JAK2 positive and negative patients was associated with an increased odds ratio for thrombosis (p=0.02). The JAK2 V617F mutation in patients with ET is associated with an increased risk of adverse cardiovascular outcomes via an increase in the leukocyte count.

Increased CD177 (PRV1) expression in thalassaemia and the underlying erythropoietic activity.

CD177 (PRV1) expression is strongly related to polycythaemia vera (PV). Whilst studying CD177 expression in PV patients and controls, individuals with beta-thalassaemia minor were found to display an elevated expression of CD177. The study was expanded to include patients with thalassaemia intermedia, sickle cell/beta-thalassaemia and thalassaemia major. CD177 expression was increased in these thalassaemic groups and correlated with their erythropoietic activity, as assessed by the measurement of serum erythropoietin and soluble transferrin receptor levels. Within this context, elevated CD177 expression is not only a specific feature of PV but may be an indicator of increased erythropoietic activity in thalassaemia syndromes.

Management of hypereosinophilic syndrome: a prospective study in the era of molecular genetics.

Hypereosinophilic syndrome (HES) is a heterogeneous group of disorders characterized by unexplained persistent primary eosinophilia causing end-organ damage. We conducted a prospective cohort study of patients fulfilling the diagnostic criteria for HES. Of 20 patients considered eligible for the study, 2 were found to have clonal myeloid disorders, limiting the diagnosis of "true" HES to 18 patients. No patient carried the FIP1L1-PDGFRA fusion gene or other imatinib-responsive translocations. A clonal interleukin-5-producing T-cell population was not detected in any patient. Common manifestations at presentation were pulmonary, cutaneous, and neurologic involvement; serositis; and gastrointestinal involvement. Only 3 patients developed cardiac involvement. Fifteen of the HES patients were administered first-line combined treatment with steroids and hydroxyurea. Nine patients achieved complete response, while 6 attained only partial response. Imatinib was administered to 3 HES patients who had been pretreated with steroids, resulting in complete hematologic and clinical response in 2 patients and no response at all in 1. Further treatment of the latter patient with steroids and hydroxyurea also proved ineffective. We conclude that the therapeutic approach should be individualized according to molecular findings. We consider the coadministration of corticosteroids and hydroxyurea to be an effective combination for the treatment of FIP1L1-PDGFRA-negative HES.

Switch in X-inactivation in a JAK2 V617F-negative case of polycythemia vera with two acquired X-autosome translocations.

We report a JAK2 V617F-negative case of polycythemia vera with two acquired balanced X-autosome translocations and no history of previous exposure to chemo/radiotherapy. The patient's first clone carried a novel translocation t(X;15)(q24;q13) as a sole abnormality. The second clone exhibited an additional translocation, t(X;20)(q13;q13.3), which is a rare recurrent abnormality in myeloid malignancies. This is the first report of a hematological disorder with both X chromosomes being translocated. Late replication studies revealed a switch in X-inactivation from the X chromosome involved in t(X;15) (first clone) to the X chromosome involved in the t(X;20)(q13;q13.3) (second clone). The inactivation of the translocated X chromosomes could provide potential for the inactivation of the adjacent autosomal regions, resulting in epigenetic gene silencing.

Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders.

The analysis of rare chromosomal translocations in myeloproliferative disorders has highlighted the importance of aberrant tyrosine kinase signaling in the pathogenesis of these diseases. Here we have investigated samples from 679 patients and controls for the nonreceptor tyrosine kinase JAK2 V617F mutation. Of the 480 myeloproliferative disorder (MPD) samples, the proportion of positive cases per disease subtype was 30 (20%) of 152 for atypical or unclassified MPD, 2 of 134 (2%) for idiopathic hypereosinophilic syndrome, 58 of 72 (81%) for polycythemia vera, 24 of 59 (41%) essential thrombocythemia (ET), and 15 of 35 (43%) for idiopathic myelofibrosis. V617F was not identified in patients with systemic mastocytosis (n = 28), chronic or acute myeloid leukemia (n = 35), secondary erythrocytosis (n = 4), or healthy controls (n = 160). Homozygosity for V617F was seen in 43% of mutant samples and was closely correlated with chromosome 9p uniparental disomy. Homozygosity was significantly less common in ET compared with other MPD subtypes. In 53 cases analyzed, the median level of PRV1 expression was significantly higher in V617F-positive cases compared with cases without the mutation. We conclude that V617F is widespread in MPDs. Detection of this acquired mutation is likely to have a major impact on the way patients with MPD are diagnosed, as well as serving as an obvious target for signal transduction therapy.