Characteristics And Clinical Correlations Of NSD1-NUP98 Fusion Gene And BCOR Mutation In BCR-ABL Negative Myeloproliferative Neoplasms

Background and objectivePolycythemia vera(PV),essential thrombocythemia(ET)and primary myelofibrosis(PMF)are three kinds of typical MPN in which BCR-ABL fusion gene is negative with a risk of transformation to acute myeloid leukemia(AML).The early diagnosis,assessment of symptoms,prognostic assessment,and therapeutic strategy for part of MPN are still critical issues which required further exploration for clinicians to meet the challenge.NUP98-NSD1 gene is fused by NSD1(nuclear receptor binding SET domain protein 1)and NUP98 which plays a non-negligible role in the regulation of malignant tumors.There could be splice site mutation as well as base deletion mutation in the 11th exon of BCOR(BCL6 corepressor)which is related to development of tumors.Recently,some studies have indicated that NSD1-NUP98 fusion as well as BCOR mutation participates in abnormality of neoplastic hematologic disorders,such as acute non-lymphocytic leukemia(AML)and myelodysplastic syndrome.Yet,there is no relevant data confirming the relationship between NSD1-NUP98 fusion or BCOR mutation and MPN nationally and internationally.The aim of the current study was to investigate the frequency of NSD1-NUP98 fusion and BCOR mutation,as well as the correlation with BCR-ABL-negative MPN and further to confirm the pathogenic mechanism and find efficiently novel targeted targets for MPN patients.Materials and MethodsOne hundred samples of bone marrow associated with BCR-ABL-negativ e MPN patients were obtained from Hunan Provincial People’ s Hospital and other National Medical Institutions from September 2014 to December 2016.Reverse Transcription-Polymerase Chain reaction(RT-PCR)and Polymerase chain reaction(PCR)were applied to detect the status of NSD1-NUP98 and BCOR mutation respectively.The PCR products in which the target band were confirmed by sampling agarose gel electrophoresis were supported to be further sequenced.The outcomes of the NSD1-NUP98 and BCOR mutation were analyzed with the clinical phenotype like age,sex,white blood cell count,platelet count.hemoglobin level,splenomegaly,thrombosis,and prognosis of disease.Results1、NSD1-NUP98 gene fusion was detected in 5 of 100 patients who was newly diagnosed as BCR-ABL-negative MPN with the positive rate of 5%.The positive rates of PV,ET and MPF were 4.8%,3.0%and 6.5%respectively,without significant difference among the three groups(P>0.05).BCOR mutation was detected in 3 of 100 patients with the positive rate of 3%.The positive rates of ET and MPF were 3.0%and 4.3%respectively,without significant difference between the two groups(P>0.05).NSD1-NUP98 fusion and BCOR mutation did not occur in the same sample.2、The mean age of patients associated with NSD1-NUP98 fusion gene was(46.00 ± 3.87)years old,which was significantly lower than that of negative ones with(60.68+11.93)years old(P<0.05).The mean age of patients in BCOR mutation group and wild type group were(62.00+15.62)and(59.89 ± 12.06)years old respectively.There was no significant difference between the two groups(P>0.05).3、There was no significant difference between the NSD1-NUP98 fusion(P>0.05)or BCOR mutation(P>0.05)positive and negative patients in the sex as well as blood cell counts.4、The frequency of NSD1-NUP98 fusion was 11.1%in the splenomegaly group which was higher than that of the non-splenomegaly group(1.6%)with statistically significant difference(P<0.05).The frequency of BCOR mutation in the splenomegaly group was 8.3%,which was significantly higher in the non-splenomegaly group(0%)(P<0.05).5、Twelve patients were developed with thrombosis.There were 3 cases with thrombosis in NSD1-NUP98 fusion gene positive group,and the incidence of thrombosis was significantly higher compared with the negative group(P<0.05).There was no BCOR mutation detected in the patients who experienced with thrombosis.6、There was only 1 patient in 100 MPN who developed with acute myeloid leukemia during the follow-up period,while 1 PV patient as well as 1 ET patient occurred bone marrow fibrosis.There were no NSD1-NUP98 fusion gene and BCOR gene mutation detected in these patients.7、There were only 4 in 73 patients who had chromosome examination revealed with abnormal karyotype with the overall incidence of 5.5%.No NSD1-NUP98 fusion and BCOR mutation were detected in the above patients.GonclusionsNSD1-NUP98 fusion gene as well as BCOR mutations could occur in BCR-ABL-negative MPN patients.The patients associated with NSD1-NUP98 fusion are prone to be young and develop with splenomegaly and thrombotic events,and BCOR mutations ones are prone to have splenomegaly.There are no correlations between NSD1-NUP98 fusion gene or BCOR mutations and sex as well as blood cell counts at the time of initial diagnosis.The discovery of NSD1-NUP98 fusion gene and BCOR mutant could improve the diagnosis,treatment decision and prognostic assessment of BCR-ABL negative MPN.