Molecular Biological Characteristics Of Myeloproliferative Tumors And Myelodysplastic Syndromes / Myeloproliferative Tumors

Objective:To investigate the relationship between the mutational status of CALR, JAK2 and MPL gene and the clinical features of polycythemia vera(PV) and primary myelofibrosis(PMF)patients with these mutations.Method:Using PCR combined with directly sequencing, we identified somatic mutations of CALR, JAK2 V617 F, JAK2 exon 12 and MPL W515L/K in 48 cases of patients with PV and 33 cases of patients with PMF whose clinical features were also studied.Result:In 48 cases of patients with PV, patients harbouring JAK2 V617 F, JAK2 exon 12 mutation accounted for 81.3%(39/48) and 0%(0/48) respectively. In 33 cases of patients with PMF, patients harbouring CALR, JAK2 V617 F, JAK2 exon 12, MPL W515L/K mutation were 12.1%(4/33), 60.6%(20/33), 0(0%) and 0%(0/33), respectively. These mutations were found existing exclusively. In PV patients, white blood cell(WBC) and platelets(Plt) count of JAK2 V617 F mutated group were higher than that of wild-type(wt) JAK2 V617 F group,while the level of hemoglobin(Hb) were higher than wt JAK2 V617 F group(P<0.05).There was no significant difference between JAK2 V617 F mutated and wide-type JAK2 V617 F group in frequency of thromboembolic events、risk stratification and overall survival(P>0.05).Compared to CALR mutated patients, the level of Hb of JAK2 V617 F mutated patients were significantly higher in PMF patients(P<0.05). According to the risk stratification, patients with JAK2 V617 F mutation were higher than triple-negative mutated patients(P<0.05). There was no significant difference between JAK2 V617 F mutated, CALR mutated and triple-negative group in frequency of thromboembolic events and overall survival(P>0.05).Conclusion: In BCR-ABL negtive patients with MPN, the proliferative level of bone marrow, risk of thromboembolic events and stratification were lower in CALR mutated patients than JAK2 V617 F mutated group. The pathogenic mechanism of mutated gene should be further investigated in the future.Objective: To investigate the gene mutation of CSF3 R, SETBP1 and SRSF2 and the clinical features in chronic neutrophilic leukemia(CNL) and chronic myelomonocytic leukemia(CMML) patients.Method : CSF3 R exons 14–17, SETBP1 and SRSF2 were sequenced in 10 WHO-defined CNL patients and 56 WHO-defined CMML patients whose clinical features were also studied.Result: In 10 cases of patients with CNL, 8(8/10, 80%) patients harbouring CSF3 R mutation and 7(7/8,87.5%) patients were CSF3 R T618I, two of which also had compound mutation(T618I/W818 X and T618I/Q749X). What’s more, one( T618I/Q749 X, 1/8, 12.5%) of them also expressed SETBP1 mutation. In 56 cases of patients with CMML, 14(14/56, 25%) patients harbouring SRSF2 mutation, 4(4/56, 7.1%) patients harbouring CSF3 R mutation and 3(3/56, 5.3%) patients harbouring SETBP1 mutation. In CMML, compared to wild-type(wt) SRSF2 patients, SRSF2 mutated patients appeared to have more SETBP1 mutation[1/14(7.1%) vs.2/42(4.8%)](P>0.05); and less CSF3 R mutation[0/14(0%) vs.4/42(9.5%)](P<0.001). The characteristics such as age, gender, WHO category, FAB category, karyotype and blood cell counts did not reveal any difference betweenSRSF2-mutated and SRSF2 wild-type patients. SRSF2-mutated patients and SETBP1-mutated patients have shorter progression-free survival(PFS) when compared with those with wt-SRSF2(P<0.001) and wt-SETBP1(P=0.02). At the same time, overall survival were also inferior in patients with either SRSF2 or SETBP1 mutation(P<0.001 both) compared with those with wt-SRSF2 or wt-SETBP1. No significant difference of PFS and overall survival(OS) between CSF3 R mutated and wt CSF3 R patients were observed. In multivariate analysis, SRSF2 mutation was an independent negative predictor for OS(P = 0.028; HR = 3.307(95%CI:1.137-9.614))and PFS(P = 0.001; RR = 15.431(95%CI:3.041-78.312));SETBP1 mutation was also an independent negative predictor for OS(P = 0.034; RR = 9.492(95%CI:1.183-76.128)).Conclusion: The majority of patients with WHO-defined CNL have oncogenic mutations in CSF3 R. The CSF3 R T618I mutation is a highly sensitive and specific molecular marker of CNL. Mutations in SRSF2 are common in CMML and may be of prognostic significance. As a non-specific molecular marker, SETBP1 was found in CNL, CMML and other blood cancers, which was a poor prognosis significance.