Mutations of spliceosome components are common in myeloid neoplasms. One of the affected genes, PRPF8, encodes the most evolutionarily conserved spliceosomal protein. We identified either recurrent somatic PRPF8 mutations or hemizygous deletions in 15/447 and 24/450 cases, respectively. Fifty percent of PRPF8 mutant and del(17p) cases were found in AML and conveyed poor prognosis. PRPF8 defects correlated with increased myeloblasts and ring sideroblasts in cases without SF3B1 mutations. Knockdown of PRPF8 in K562 and CD34+ primary bone marrow cells increased proliferative capacity. Whole-RNA deep sequencing of primary cells from patients with PRPF8 abnormalities demonstrated consistent missplicing defects. In yeast models, homologous mutations introduced into Prp8 abrogated a block experimentally produced in the second step of the RNA splicing process, suggesting that the mutants have defects in proof-reading functions. In sum, the exploration of clinical and functional consequences suggests that PRPF8 is a novel leukemogenic gene in myeloid neoplasms with a distinct phenotype likely manifested through aberrant splicing.

Introduction: The haemostatic system can be significantly altered by haematological malignancies and their treatment. Abnormal haemostatic values can be detected in about 50% of advanced disease and these underlie the characteristic thrombotic and haemorrhagic diasthesis seen in these patients. Haemostatic indices in Philadelphia Positive and Negative Chronic Granulocytic Leukaemia Patients were investigated to determine their clinical relevance and possible association. Patients and Methods: Fifteen newly diagnosed Philadelphia positive (ph+ve) and 11 Philadelphia negative (ph-ve) CGL patients were studied longitudinally along with 20 healthy controls. Baseline blood samples were collected and analysed before commencing first cycle chemotherapy and after each successive cycle up to sixth cycle .Samples were analysed for haemoglobin concentration (Hb), leucocytes count (WBC), platelet count (PLT), prothrombin time (PT), activated partial thromboplastin time (APTT), plasma fibrinogen (PFC), and euglobulin lysis time (ELT) using standard techniques. Results were analysed statistically using Student’s t-test. Probability values <0.05 were significant. Results: Ph-ve CGL patients had significantly higher baseline levels of PFC and ELT compared to Ph+ve patients (P < 0.05). Ph+ve CGL patients with complete remission had a significantly lower baseline level of PFC compared to those without remission (P < 0.05). There were no significant changes in PFC and ELT in both groups after the 4th cycle of chemotherapy (P > 0.05). Conclusion: Philadelphia negativity may be a potential risk factor for increased thrombotic tendencies in CGL patients. PFC may be a useful predictive marker of haemostatic activation in these patients.