Clinical significance of CD34⁺CD117^dim/CD34⁺CD117^bri myeloblast-associated gene expression in t(8;21) acute myeloid leukemia

Abstract

t(8;21)(q22;q22) acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy with a high relapse rate in China. Two leukemic myeloblast populations (CD34⁺CD117^dim and CD34⁺CD117^bri) were previously identified in t(8;21) AML, and CD34⁺CD117^dim cell proportion was determined as an independent factor for this disease outcome. Here, we examined the impact of CD34⁺CD117^dim/CD34⁺CD117^bri myeloblast-associated gene expression on t(8;21) AML clinical prognosis. In this study, 85 patients with t(8;21) AML were enrolled. The mRNA expression levels of CD34⁺CD117^dim-associated genes (LGALS1, EMP3, and CRIP1) and CD34⁺CD117^bri-associated genes (TRH, PLAC8, and IGLL1) were measured using quantitative reverse transcription PCR. Associations between gene expression and clinical outcomes were determined using Cox regression models. Results showed that patients with high LGALS1, EMP3, or CRIP1 expression had significantly inferior overall survival (OS), whereas those with high TRH or PLAC8 expression showed relatively favorable prognosis. Univariate analysis revealed that CD19, CD34⁺CD117^dim proportion, KIT mutation, minimal residual disease (MRD), and expression levels of LGALS1, EMP3, CRIP1, TRH and PLAC8 were associated with OS. Multivariate analysis indicated that KIT mutation, MRD and CRIP1 and TRH expression levels were independent prognostic variables for OS. Identifying the clinical relevance of CD34⁺CD117^dim/CD34⁺CD117^bri myeloblast-associated gene expression may provide new clinically prognostic markers for t(8;21) AML.

Keywords

t(8 / 21)(q22 / q22) AML / CD34⁺CD117^dim/ CD34⁺CD117^bri cell population / gene expression / prognosis

References

[1] Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med 2015; 373(12): 1136–1152

[2] Wang YY, Zhou GB, Yin T, Chen B, Shi JY, Liang WX, Jin XL, You JH, Yang G, Shen ZX, Chen J, Xiong SM, Chen GQ, Xu F, Liu YW, Chen Z, Chen SJ. AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec. Proc Natl Acad Sci USA 2005; 102(4): 1104–1109

[3] Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Löwenberg B, Bloomfield CD. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017; 129(4): 424–447

[4] Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, Potter NE, Heuser M, Thol F, Bolli N, Gundem G, Van Loo P, Martincorena I, Ganly P, Mudie L, McLaren S, O’Meara S, Raine K, Jones DR, Teague JW, Butler AP, Greaves MF, Ganser A, Döhner K, Schlenk RF, Döhner H, Campbell PJ. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 2016; 374(23): 2209–2221

[5] Faber ZJ, Chen X, Gedman AL, Boggs K, Cheng J, Ma J, Radtke I, Chao JR, Walsh MP, Song G, Andersson AK, Dang J, Dong L, Liu Y, Huether R, Cai Z, Mulder H, Wu G, Edmonson M, Rusch M, Qu C, Li Y, Vadodaria B, Wang J, Hedlund E, Cao X, Yergeau D, Nakitandwe J, Pounds SB, Shurtleff S, Fulton RS, Fulton LL, Easton J, Parganas E, Pui CH, Rubnitz JE, Ding L, Mardis ER, Wilson RK, Gruber TA, Mullighan CG, Schlenk RF, Paschka P, Döhner K, Döhner H, Bullinger L, Zhang J, Klco JM, Downing JR. The genomic landscape of core-binding factor acute myeloid leukemias. Nat Genet 2016; 48(12): 1551–1556

[6] Yushu H, Shougeng B, Zhijian X, Yingchang M, Chao HZ. Acute myeloid leukemia M2b. Haematologica 1999; 84(3): 193–194

[7] Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, Wheatley K, Harrison CJ, Burnett AK; the National Cancer Research Institute Adult Leukaemia Working Group. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 116(3): 354–365

[8] Jiang L, Li XP, Dai YT, Chen B, Weng XQ, Xiong SM, Zhang M, Huang JY, Chen Z, Chen SJ. Multidimensional study of the heterogeneity of leukemia cells in t(8;21) acute myelogenous leukemia identifies the subtype with poor outcome. Proc Natl Acad Sci USA 2020; 117(33): 20117–20126

[9] Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 2012; 16(5): 284–287

[10] The Cancer Genome Atlas Research Network . Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368(22): 2059–2074

[11] Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, Sabedot TS, Malta TM, Pagnotta SM, Castiglioni I, Ceccarelli M, Bontempi G, Noushmehr H. TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res 2016; 44(8): e71

[12] Zhu HH, Zhang XH, Qin YZ, Liu DH, Jiang H, Chen H, Jiang Q, Xu LP, Lu J, Han W, Bao L, Wang Y, Chen YH, Wang JZ, Wang FR, Lai YY, Chai JY, Wang LR, Liu YR, Liu KY, Jiang B, Huang XJ. MRD-directed risk stratification treatment may improve outcomes of t(8;21) AML in the first complete remission: results from the AML05 multicenter trial. Blood 2013; 121(20): 4056–4062

[13] Schnittger S, Weisser M, Schoch C, Hiddemann W, Haferlach T, Kern W. New score predicting for prognosis in PML-RARA⁺, AML1-ETO⁺, or CBFBMYH11⁺ acute myeloid leukemia based on quantification of fusion transcripts. Blood 2003; 102(8): 2746–2755

[14] Leroy H, de Botton S, Grardel-Duflos N, Darre S, Leleu X, Roumier C, Morschhauser F, Lai JL, Bauters F, Fenaux P, Preudhomme C. Prognostic value of real-time quantitative PCR (RQ-PCR) in AML with t(8;21). Leukemia 2005; 19(3): 367–372

[15] Gale RE, Hills R, Pizzey AR, Kottaridis PD, Swirsky D, Gilkes AF, Nugent E, Mills KI, Wheatley K, Solomon E, Burnett AK, Linch DC, Grimwade D; the NCRI Adult Leukaemia Working Party. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood 2005; 106(12): 3768–3776

[16] Noguera NI, Breccia M, Divona M, Diverio D, Costa V, De Santis S, Avvisati G, Pinazzi MB, Petti MC, Mandelli F, Lo Coco F. Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia 2002; 16(11): 2185–2189

[17] Kuchenbauer F, Schoch C, Kern W, Hiddemann W, Haferlach T, Schnittger S. Impact of FLT3 mutations and promyelocytic leukaemia-breakpoint on clinical characteristics and prognosis in acute promyelocytic leukaemia. Br J Haematol 2005; 130(2): 196–202

[18] Jiao B, Wu CF, Liang Y, Chen HM, Xiong SM, Chen B, Shi JY, Wang YY, Wang JH, Chen Y, Li JM, Gu LJ, Tang JY, Shen ZX, Gu BW, Zhao WL, Chen Z, Chen SJ. AML1-ETO9a is correlated with C-KIT overexpression/mutations and indicates poor disease outcome in t(8;21) acute myeloid leukemia-M2. Leukemia 2009; 23(9): 1598–1604

[19] Willekens C, Blanchet O, Renneville A, Cornillet-Lefebvre P, Pautas C, Guieze R, Ifrah N, Dombret H, Jourdan E, Preudhomme C, Boissel N. Prospective long-term minimal residual disease monitoring using RQ-PCR in RUNX1-RUNX1T1-positive acute myeloid leukemia: results of the French CBF-2006 trial. Haematologica 2016; 101(3): 328–335

[20] Christen F, Hoyer K, Yoshida K, Hou HA, Waldhueter N, Heuser M, Hills RK, Chan W, Hablesreiter R, Blau O, Ochi Y, Klement P, Chou WC, Blau IW, Tang JL, Zemojtel T, Shiraishi Y, Shiozawa Y, Thol F, Ganser A, Löwenberg B, Linch DC, Bullinger L, Valk PJM, Tien HF, Gale RE, Ogawa S, Damm F. Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients. Blood 2019; 133(10): 1140–1151

[21] Wang YW, Cheng HL, Ding YR, Chou LH, Chow NH. EMP1, EMP 2, and EMP3 as novel therapeutic targets in human cancer. Biochim Biophys Acta Rev Cancer 2017; 1868(1): 199–211

[22] Çiftçiler R, Haznedaroğlu IC, Sayınalp N, Özcebe O, Aksu S, Demiroğlu H, Göker H, Malkan UY, Büyükaşık Y. The impact of early versus late platelet and neutrophil recovery after induction chemotherapy on survival outcomes of patients with acute myeloid leukemia. Turk J Haematol 2020; 37(2): 116–120

[23] He G, Zhu H, Yao Y, Chai H, Wang Y, Zhao W, Fu S, Wang Y. Cysteine-rich intestinal protein 1 silencing alleviates the migration and invasive capability enhancement induced by excessive zinc supplementation in colorectal cancer cells. Am J Transl Res 2019; 11(6): 3578–3588

[24] Li HG, Zhao LH, Zhang ZH, Liu JZ, Ren K, Li SY, Su ZJ. The impact of cysteine-rich intestinal protein 1 (CRIP1) on thyroid carcinoma. Cell Physiol Biochem 2017; 43(5): 2037–2046

[25] Zhang L, Zhou R, Zhang W, Yao X, Li W, Xu L, Sun X, Zhao L. Cysteine-rich intestinal protein 1 suppresses apoptosis and chemosensitivity to 5-fluorouracil in colorectal cancer through ubiquitin-mediated Fas degradation. J Exp Clin Cancer Res 2019; 38(1): 120

[26] Ye C, Ma S, Xia B, Zheng C. Weighted gene coexpression network analysis identifies cysteine-rich intestinal protein 1 (CRIP1) as a prognostic gene associated with relapse in patients with acute myeloid leukemia. Med Sci Monit 2019; 25: 7396–7406

[27] Chou FC, Chen HY, Kuo CC, Sytwu HK. Role of galectins in tumors and in clinical immunotherapy. Int J Mol Sci 2018; 19(2): E430

[28] Feng Y, Ji D, Huang Y, Ji B, Zhang Y, Li J, Peng W, Zhang C, Zhang D, Sun Y, Xu Z. TGM3 functions as a tumor suppressor by repressing epithelialtomesenchymal transition and the PI3K/AKT signaling pathway in colorectal cancer. Oncol Rep 2020; 43(3): 864–876

[29] Wang YS, Li H, Li Y, Zhang S, Jin YH. (20S)G-Rh2 inhibits NF-kB regulated epithelial-mesenchymal transition by targeting annexin A2. Biomolecules 2020; 10(4): E528

[30] Schliekelman MJ, Taguchi A, Zhu J, Dai X, Rodriguez J, Celiktas M, Zhang Q, Chin A, Wong CH, Wang H, McFerrin L, Selamat SA, Yang C, Kroh EM, Garg KS, Behrens C, Gazdar AF, Laird-Offringa IA, Tewari M, Wistuba II, Thiery JP, Hanash SM. Molecular portraits of epithelial, mesenchymal, and hybrid states in lung adenocarcinoma and their relevance to survival. Cancer Res 2015; 75(9): 1789–1800

[31] Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133(4): 704–715

[32] Rahimi M, Sharifi-Zarchi A, Firouzi J, Azimi M, Zarghami N, Alizadeh E, Ebrahimi M. An integrated analysis to predict micro-RNAs targeting both stemness and metastasis in breast cancer stem cells. J Cell Mol Med 2019; 23(4): 2442–2456

[33] Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, Shen L, Fan Y, Giri U, Tumula PK, Nilsson MB, Gudikote J, Tran H, Cardnell RJ, Bearss DJ, Warner SL, Foulks JM, Kanner SB, Gandhi V, Krett N, Rosen ST, Kim ES, Herbst RS, Blumenschein GR, Lee JJ, Lippman SM, Ang KK, Mills GB, Hong WK, Weinstein JN, Wistuba II, Coombes KR, Minna JD, Heymach JV. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res 2013; 19(1): 279–290

[34] Tan TZ, Miow QH, Miki Y, Noda T, Mori S, Huang RY, Thiery JP. Epithelial-mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients. EMBO Mol Med 2014; 6(10): 1279–1293

[35] Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2014; 15(3): 178–196

[36] Stavropoulou V, Kaspar S, Brault L, Sanders MA, Juge S, Morettini S, Tzankov A, Iacovino M, Lau IJ, Milne TA, Royo H, Kyba M, Valk PJM, Peters AHFM, Schwaller J. MLL-AF9 expression in hematopoietic stem cells drives a highly invasive AML expressing EMT-related genes linked to poor outcome. Cancer Cell 2016; 30(1): 43–58

[37] Bullinger L, Rücker FG, Kurz S, Du J, Scholl C, Sander S, Corbacioglu A, Lottaz C, Krauter J, Fröhling S, Ganser A, Schlenk RF, Döhner K, Pollack JR, Döhner H. Gene-expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia. Blood 2007; 110(4): 1291–1300

[38] Hsu CH, Nguyen C, Yan C, Ries RE, Chen QR, Hu Y, Ostronoff F, Stirewalt DL, Komatsoulis G, Levy S, Meerzaman D, Meshinchi S. Transcriptome profiling of pediatric core binding factor AML. PLoS One 2015; 10(9): e0138782

[39] Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, Cahill DP, Nahed BV, Curry WT, Martuza RL, Louis DN, Rozenblatt-Rosen O, Suvà ML, Regev A, Bernstein BE. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 2014; 344(6190): 1396–1401

[40] Li S, Garrett-Bakelman FE, Chung SS, Sanders MA, Hricik T, Rapaport F, Patel J, Dillon R, Vijay P, Brown AL, Perl AE, Cannon J, Bullinger L, Luger S, Becker M, Lewis ID, To LB, Delwel R, Löwenberg B, Döhner H, Döhner K, Guzman ML, Hassane DC, Roboz GJ, Grimwade D, Valk PJ, D’Andrea RJ, Carroll M, Park CY, Neuberg D, Levine R, Melnick AM, Mason CE. Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia. Nat Med 2016; 22(7): 792–799

[41] Jia Y, Ying X, Zhou J, Chen Y, Luo X, Xie S, Wang QC, Hu W, Wang L. The novel KLF4/PLAC8 signaling pathway regulates lung cancer growth. Cell Death Dis 2018; 9(6): 603

[42] Zou L, Chai J, Gao Y, Guan J, Liu Q, Du JJ. Down-regulated PLAC8 promotes hepatocellular carcinoma cell proliferation by enhancing PI3K/Akt/GSK3β/Wnt/β-catenin signaling. Biomed Pharmacother 2016; 84: 139–146

[43] Mao M, Chen Y, Jia Y, Yang J, Wei Q, Li Z, Chen L, Chen C, Wang L. PLCA8 suppresses breast cancer apoptosis by activating the PI3k/AKT/NF-kB pathway. J Cell Mol Med 2019; 23(10): 6930–6941

Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 81800147), Shanghai Sailing Program (No. 18YF1413700), the National Key Research and Development Plan of China (No. 2018YFA0107800), the National Natural Science Foundation of China (No. 81890994), the National Key Research and Development Plan of China (No. 2017YFA0506200), and the Innovative Research Team of High-level Local Universities in Shanghai.

Compliance with ethics guidelines

Xueping Li, Yuting Dai, Bing Chen, Jinyan Huang, Saijuan Chen, and Lu Jiang declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. This study was approved by the Ruijin Hospital Review Board and was in accordance with the principle of the Helsinki Declaration II.

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Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-021-0836-7 and is accessible for authorized users.

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