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LETTERS TO THE EDITORTurk J Hematol 2021;38:228-245Long Non-Coding RNA MALAT1 Contributed to the Proliferation ofPNH Clone in Paroxysmal Nocturnal Hemoglobinuria PatientsUzun Kodlama Yapmayan RNA, MALAT1, Paroksismal Noktürnal Hemoglobinüri HastalarındaPNH Klonal Proliferasyonuna Katkı SağlarHonglei Wang*, Yingying Chen*, Hui Liu, Zhaoyun Liu, Rong Fu*These authors contributed equally to this work.Tianjin Medical University General Hospital, Department of Hematology, Tianjin, ChinaTo the Editor,Paroxysmal nocturnal hemoglobinuria (PNH) is an acquiredclonal disorder of hematopoietic stem cells caused bysomatic mutation of the phosphatidylinositol glycan A gene(PIG-A) on chromosome Xp22.1 [1]. The PIG-A mutation isnecessary but insufficient to explain PNH clone proliferation.The mechanism of the proliferative advantage of the PNHclone has not yet been clarified. At present, studies on themechanism of PNH clone proliferation are mainly focusedon protein-coding genes, while the function and clinicalsignificance of non-coding RNAs (ncRNAs), and in particularlong ncRNAs (LncRNAs), in PNH remain unknown. MALAT1 isone of the most extensively studied LncRNAs. It was foundlocalized in the nucleus and expressed in a variety of tissues[2]. MALAT1 can regulate cell proliferation, differentiation,apoptosis, migration, and autophagy, among others [3].MALAT1 has been demonstrated to be involved in manycancers, cardio-cerebrovascular disease, and hematologicalmalignancies. However, knowledge of the action of MALAT1in PNH is still lacking. The purpose of our study was toinvestigate the role of MALAT1 in PNH clone proliferationand to find a new therapeutic direction for PNH.A total of 30 PNH patients, including 22 PNH patients and 8aplastic anemia (AA)-PNH patients, were enrolled in our studyaccording to international PNH Study Group Criteria [4]. CD59 –and CD59 + granulocytes and monocytes were obtained byflow cytometry (Figures 1A and 1B). MALAT1 expressions wereverified for these 30 PNH patients by quantitative real-timepolymerase chain reaction (qRT-PCR). The clinical features of thePNH patients, primers of MALAT1, and methods of cell sortingand qRT-PCR are available from the authors as supplementarydata. Correlations were analyzed with clinical indexes, includinghemoglobin (Hb), white blood cell count (WBC), platelet count(PLT), reticulocytes (Ret), lactate dehydrogenase (LDH), totalbilirubin (TBIL), and PNH clones.As the results of qRT-PCR showed, MALAT1 (3.070±2.503)expressions in CD59 – cells were consistently higher than thosein CD59+ cells (1.281±1.246, p=0.0004) among these 30 PNHpatients (Figure 1C).High expression of MALAT1 was negatively correlated with Hblevel (r=-0.3894, p=0.0334) and positively correlated with thepercentage of Ret (r=0.4481, p=0.0168), LDH levels (r=0.6244,p=0.0307), and CD59 – granulated and monocyte cell ratio(r=0.5188, p=0.0049) (Figure 1D).The level of MALAT1 in PNH clone cells was found to besignificantly increased and was correlated with clinical indicatorsof PNH. The molecular functions of MALAT1 include alternativesplicing, transcriptional regulation, and competing endogenousRNA functions. MALAT1 was shown to bind alternative splicingfactor SRSF1 in hepatocellular carcinoma development [5].In another study, MALAT1 promoted the proliferation andimatinib resistance of chronic myeloid leukemia cells via theMALAT1/miR-328 axis [6]. MALAT1 downregulated miR-181a-5pthrough the Hippo-YAP signaling pathway, resulting in regulationof myeloma cell proliferation [7]. MALAT1 could also inducetolerogenic dendritic cells and immune tolerance in autoimmunediseases by regulating the miRNA-155/DC-SIGH/IL10 axis [8].These results illustrate that MALAT1 plays an important role notonly in malignant tumors but also in benign diseases.The characteristics of clonal dynamics and selection forces ofPNH clones are similar to those of tumors. Thus, we predictthat MALAT1 may have an important function in contributingto proliferation advantages and restraining apoptosis in PNHprogression. The mechanism remains to be further studied.Keywords: Paroxysmal nocturnal hemoglobinuria, LncRNA,Clone proliferation, MALAT1Anahtar Sözcükler: Paroksismal noktürnal hemoglobinüri,LncRNA, Klonal proliferasyon, MALAT1Informed Consent: Our study complied with the InternationalEthical Guidelines for Biomedical Research Involving HumanSubjects (2002) developed by the Council for InternationalOrganizations of Medical Sciences (CIOMS) in collaboration236
Turk J Hematol 2021;38:228-245LETTERS TO THE EDITORFigure 1. A) The cells of 30 PNH patients were sorted by flow cytometry to obtain CD59 – and CD59 + granulocytes and monocytes.Granulocytes and monocytes were selected as sorting objects in the first flow diagram, and CD59 – (P2) and CD59 + (P3) granulocytesand monocytes were selected in the second flow diagram by CD59 sorting. B) Sorting purity of the CD59 – and CD59 + granulocytes andmonocytes. The sorting purity is about 90%. C) MALAT1 expression of the CD59 – and CD59 + cells in 30 PNH patients. D) Correlationanalysis between MALAT1 expression and clinical data. The expression of MALAT1 was negatively correlated with the proportion of thelevel of Hb and positively correlated with the percentage of Ret, LDH levels, and the proportion of PNH clones.with the World Health Organization (WHO) and was approvedby the Ethics Committee of Tianjin Medical University.Authorship ContributionsDesign: R.F.; Data Collection or Processing: H.W., Y.C., H.L., Z.L.;Writing: H.W., Y.C.Conflict of Interest: No conflict of interest was declared by theauthors.Financial Disclosure: This work was supported by the NationalNatural Science Foundation of China (Grant nos. 81770110,81900131, 82000128), the Tianjin Municipal Natural ScienceFoundation (Grant nos. 18JCYBJC27200, 18JCQNJC80400), andthe Tianjin Education Commission Research Project (2018KJ043,2018KJ045).References1. Hill A, DeZern AE, Kinoshita T, Brodsky RA. Paroxysmal nocturnalhaemoglobinuria. Nat Rev Dis Primers 2017;3:17028.2. Lei L, Chen J, Huang J, Lu J, P ei S, Ding S, Kang L, Xiao R, Zeng Q. Functionsand regulatory mechanisms of metastasis-associated lung adenocarcinomatranscript 1. J Cell Physiol 2018;234:134-151.3. Zhang X, Hamblin MH, Yin KJ. The long noncoding RNA Malat1: itsphysiological and pathophysiological functions. RNA Biol 2017;14:1705-1714.4. Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, HillmenP, Luzzatto L, Young N, Kinoshita T, Rosse W, Socié G; International PNHInterest Group. Diagnosis and management of paroxysmal nocturnalhemoglobinuria. Blood 2005;106:3699-3709.5. Malakar P, Shilo A, Mogilevsky A, Stein I, Pikarsky E, Nevo Y, BenyaminiH, Elgavish S, Zong X, Prasanth KV, Karni R. Long noncoding RNA MALAT1promotes hepatocellular carcinoma development by SRSF1 upregulationand mTOR activation. Cancer Res 2017;77:1155-1167.237
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