Nicholas C P Cross

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..Our data, therefore, provide evidence that ruxolitinib is a promising therapy for treatment of patients with JAK2 fusion genes...

..This review summarizes the established facts relating to the genetics of MPNs, but highlights recent findings and areas of controversy...

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..No difference in sequence, splicing, or expression of JAK2 was found on 46/1 compared with other haplotypes, suggesting that any functional difference of JAK2 on 46/1, if it exists, must be relatively subtle...

..7; 95% CI = 3.1-4.3) and provides a model whereby a constitutional genetic factor is associated with an increased risk of acquiring a specific somatic mutation...

..We hypothesized that hitherto unrecognized, cytogenetically cryptic tyrosine kinase fusions may be common in non-classical or atypical myeloproliferative neoplasms and related myelodysplastic/myeloproliferative neoplasms...

..We investigated these aspects in a large series of patients...

..Notably, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies...

..We conclude that MYC dysregulation by complex mechanisms is one of the major molecular events in the oncogenesis of PCL...

..We conclude that PDGFRB fuses to diverse partner genes in atypical myeloproliferative neoplasms (MPNs). Although very rare, identification of these fusions is critical for proper management of affected individuals...

..In conclusion, PDGFRA fuses to diverse partner genes in myeloid disorders. Identification of these fusions is important as they are particularly sensitive to imatinib...

..All 3 SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase activity in vitro, demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes...

..We conclude that TP53BP1-PDGFRB is a novel imatinib target in atypical chronic myeloid leukemia...

..Our data indicate that, although PV patients may benefit from imatinib or rIFNalpha, molecular responses are relatively modest...

..We conclude that acquired, transforming CBL mutations are a novel and widespread pathogenetic abnormality in morphologically related, clinically aggressive MPNs...

..Levels of STAT3 mRNA correlated with rs6503691 genotype (P<0.001) as assessed by real time quantitative PCR and therefore we conclude that rs6503691 is associated with the STAT3 expression levels and response of CML patients to IFN...

..None of the associated genetic abnormalities helped to predict for progression from MGUS or smoldering myeloma...

..007), age (P = .018), and spleen enlargement (P < .001) were significant independent indicators of survival and confirmed that only deletions spanning the ABL/BCR breakpoint were associated with an adverse prognosis (P = .039)...

..The tyrosine kinase inhibitor imatinib mesylate specifically inhibits ABL, PDGFR, and KIT kinases and has impressive clinical efficacy in BCR-ABL-positive chronic myeloid leukemia...

..Our data indicate that several PDGFRB partner genes remain to be characterized...

..Analysis of allelic methylation differences at the small nuclear ribonucleoprotein polypeptide N (SNRPN) locus differentiates the maternally and paternally inherited chromosome 15 and can be used as a diagnostic test for AS and PWS...

..Our findings thus identify a group of proteins that are important for pre-mRNA processing as fusion partners for tyrosine kinases in hematological malignancies...

..This work provides evidence that targeted therapy may be beneficial for patients with EMS...

..To determine the consequences and significance of an acquired 46XX,t(2;13;2;21)(p13;q12;q33;q11.2) in atypical chronic myeloid leukemia (aCML)...

..Mutation analysis of the KIT coding region in this family identified a novel A>T mutation at nucleotide 1547 [K509I] in exon 9 in both of the affected patients...

..Analysis of allelic methylation differences at the small nuclear ribonucleoprotein polypeptide N (SNRPN) locus can differentiate the maternally and paternally inherited chromosome 15 and can be used as a diagnostic test for AS and PWS...

..This case report provides a unique insight into the mechanisms of disease progression from smouldering multiple myeloma to multiple myeloma...

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..This approach may be adapted for other syndromes with well defined common point mutations or polymorphisms...

..Here we describe the first example of a human polymorphic in-frame fusion of two unrelated genes associated with a copy number variant...

..In one evaluable patient, ponatinib specifically reduced numbers of FGFR1-fusion gene positive colonies. Ponatinib, therefore, shows considerable promise for the treatment of patients with 8p11 myeloproliferative syndrome...

..Our findings indicate that apparently simple cytogenetic variants of t(9;22) do not always mask a cryptic BCR-ABL fusion, even when found in association with clinical and haematological indications of CML...

..Furthermore, synergistic effects are seen for combined treatment with DNA demethylating agents and histone deacetylation inhibitors, opening up the possibility of refined epigenetic treatments in the future...

..The presence of the chimeric gene was confirmed by RT-PCR, genomic DNA PCR, and FISH. These data further support the central role of deregulated FGFR1 in the pathogenesis of EMS...

..High resolution melting analysis is a rapid, sensitive and high-throughput technique that is suitable for screening for JAK2 exon 12 mutations...

..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...

..This is the first description of NUP98-LEDGF in CML and strengthens the association between disease progression in and NUP98 abnormalities...

..Although the development of resistance has been problematic, particularly in aggressive disease, the development of novel inhibitors and combination with other forms of therapy shows promise...

..The identification of ALL with rare ABL1 fusion partners is important because the leukaemia may respond to tyrosine kinase inhibitors in the same way as ALL patients with a classical BCR-ABL1 fusion gene...

..With the advent of targeted signal transduction therapy, patients with rearrangement of PDGFRB might be better classified as a distinct subgroup of MPD/MDS...

..In addition, new molecular findings need to be incorporated into disease classification systems...

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..The MELAS A3243G mutation was detected reliably at a level of 1% heteroplasmy. We conclude that Pyrosequencing is a rapid and robust method for detecting heteroplasmic mitochondrial point mutations...

..Currently, most reported methods lack one or more of these characteristics. We describe the optimization and validation of conformation-sensitive capillary electrophoresis (CSCE) for diagnostic mutation scanning...

..We conclude that human autoantigen pericentriolar material (PCM1)-JAK2 is a novel, recurrent fusion gene in hematologic malignancies. Patients with PCM1-JAK2 disease are attractive candidates for targeted signal transduction therapy...

..We used imatinib to treat a 49-year old man with atypical CMD in accelerated phase and the H4 (D10S170)-PDGFRB fusion gene. After 3 months of treatment, we observed grade 4 hematologic toxicity and a lack of response...

..After treatment with imatinib, the patient achieved hematological and cytogenetical remission, but NIN-PDGFRB mRNA remained detectable by reverse transcription-PCR...

..Screening for the FIP1L1-PDGFRA rearrangement and Asp816Val mutation will advance rational therapy decisions in SMCD...

..These findings are consistent with the hypothesis that the t(15;17) occurs by nonhomologous recombination of DNA after processing of the double-strand breaks by a dysfunctional DNA damage-repair mechanism...

..Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause...

..CONCLUSIONS: Drug-induced cleavage of DNA by topoisomerase II mediates the formation of chromosomal translocation breakpoints in mitoxantrone-related APL and in APL that occurs after therapy with other topoisomerase II poisons...

..The authors describe the clinical course of three children with HES in whom FIP1L1-PDGFRA fusion gene was studied and report the first child with this rearrangement...

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..Our data show that durable hematologic and cytogenetic responses are achieved with imatinib in patients with PDGFRB fusion-positive, BCR-ABL-negative CMPDs...

..Myocardial biopsy revealed eosinophilic infiltration and degranulation, and the cardiogenic shock was reversed with the prompt institution of corticosteroid therapy...

..These results indicate that nucleosomal targeting by MOZ and recruitment of CBP by TIF2 are critical requirements for MOZ-TIF2 transformation and indicate that MOZ gain of function contributes to leukemogenesis...

..The JAK2(V617F) mutation, which has been found in patients with myeloproliferative disorders (MPD), has not yet been evaluated in lymphoproliferative disorders by any adequately sensitive techniques...

..These findings suggest a critical role of STAT5 activation in transformation mediated by ZNF198-FGFR1...

..These results implicate different signaling pathways originating from both kinase and fusion partner in the pathogenesis of CML and EMS...

..These cases illustrate the clinical heterogeneity observed in patients with FGFR1 rearrangements and suggest that constitutively activated tyrosine kinases may be more widespread in MPDs...

..In a preliminary fluorescence in situ hybridization study, the breakpoints on chromosome 6 in two additional cases were found to be telomeric to the gene for 51 kDa FK506-binding protein (FKBP51)...

..It remains to be established what role this mutation, which gives cells a proliferative advantage, might play in the pathogenesis and prognosis of rare atypical MPD...

..Other inhibitors under development are promising candidates for effective treatment of patients with constitutive activation of JAK2, FGFR1 and imatinib-resistant KIT mutants...

..The assay is fast and easy to perform, and no special equipment other than thermocyclers is required. All these features make the assay readily and broadly applicable in clinical molecular diagnostic laboratories...

..These 2 genes and their corresponding pathways provide an important insight into the potential mechanisms by which 16q LOH confers poor prognosis...

..We recognize that our recommendations are provisional and will require revision as new evidence emerges...