Alternative polyadenylation(APA)is a post-transcriptional process that typically determines the length of mature mRNAs'3'untranslated region(3'UTR).The global shortened 3'UTR alters mRNA stability,localization,and translation and contributes to cancer progression.1 The APA characteristics and its effects on acute myeloid leukemia(AML)remain to be comprehensively described.Here,we identified churchill domain containing 1(CHURC1)as an upregulated gene with a lengthened 3'UTR in CD34+enriched AML cells compared with healthy hematopoietic stem and progenitor cells.As for APA regulation of CHURC1,we found that rs6745 and RNA binding protein TIA1 potentially contribute to the distal poly(A)site usage in cis-and transways,respectively.Mechanistically,a lengthened CHURC13'UTR affected the apoptosis of AML cells by disrupting the expression of DICER1 by sponging miR-186-5p.The chemotherapeutic sensitivity of 8 drugs was associated with CHURC1 poly(A)site usage.Overall,our analysis indicated a previously undetected gene,CHURC1,that affected AML progression through 3'UTR length change resulting from APA.Data collection and detailed analysis methods were described in the supplementary material.
Xi HuPanxiang CaoFang WangHuqin ZhangTong WangHongxing LiuXiaoming Wu
BACKGROUND Acute myeloid leukemia(AML)is a complicated disease with uncontrolled hematopoietic precursor proliferation induced by various genetic alterations.Runt-related transcription factor-1(RUNX1)is commonly disrupted by chromosomal translocations in hematological malignancies.AIM To characterize RUNX1 gene rearrangements and copy number variations in newly diagnosed adult AML patients,with an emphasis on the impact of clinical and laboratory features on the outcome.METHODS Fluorescence in situ hybridization was used to test RUNX1 gene alterations in 77 newly diagnosed adult AML cases.NPM1,FLT3/ITD,FLT3/TKD,and KIT mutations were tested by PCR.Prognostic clinical and laboratory findings were studied in relation to RUNX1 alterations.RESULTS RUNX1 abnormalities were detected by fluorescence in situ hybridization in 41.6%of patients:20.8%had translocations,22.1%had amplification,and 5.2%had deletion.Translocations prevailed in AML-M2(P=0.019)with a positive expression of myeloperoxidase(P=0.031),whereas deletions dominated in M4 and M5 subtypes(P=0.008)with a positive association with CD64 expression(P=0.05).The modal chromosomal number was higher in cases having amplifications(P=0.007)and lower in those with deletions(P=0.008).RUNX1 abnormalities were associated with complex karyotypes(P<0.001)and were mutually exclusive of NPM1 mutations.After 44 months of follow-up,RUNX1 abnormalities affected neither patients’response to treatment nor overall survival.CONCLUSION RUNX1 abnormalities were mutually exclusive of NPM1 mutations.RUNX1 abnormalities affected neither patients’response to treatment nor overall survival.
Hoda M Abd El-GhanyMona S El AshryMona S AbdellateifAhmed RabeaNada SultanOmnia Y Abd El Dayem
