A 4-gene leukemic stem cell score can independently predict the prognosis of myelodysplastic syndrome patients
Tóm tắt
Myelodysplastic syndrome (MDS) comprised a heterogeneous group of diseases. The prognosis of patients varies even in the same risk groups. Searching for novel prognostic markers is warranted. Leukemic stem cells (LSCs) are responsible for chemoresistance and relapse in leukemia. Recently, expressions of 17 genes related to stemness of LSCs were found to be associated with prognosis in acute myeloid leukemia patients. However, the clinical impact of LSC genes expressions in MDS, a disorder arising from hematopoietic stem cells, remains unclear. We analyzed expression profile of the 17 stemness-related genes in primary MDS patients and identified expression of 4 genes (LAPTM4B, NGFRAP1, EMP1, and CPXM1) were significantly correlated with overall survival (OS). We constructed an LSC4 scoring system based on the weighted sums of the expression of 4 genes and explored its clinical implications in MDS patients. Higher LSC4 scores were associated with higher revised International Prognostic Scoring System (IPSS-R) scores, complex cytogenetics, and mutations in RUNX1, ASXL1, and TP53. High-score patients had significantly shorter OS and leukemia-free survival (LFS), which was also confirmed in 2 independent validation cohorts. Subgroup analysis revealed the prognostic significance of LSC4 scores for OS remained valid across IPSS-R lower- and higher-risk groups. Furthermore, higher LSC4 score was an independent adverse risk factor for OS and LFS in multivariate analysis. In summary, LSC4 score can independently predict prognosis in MDS patients irrespective of IPSS-R risks and may be used to guide the treatment of MDS patients, especially lower-risk group in whom usually only supportive treatment is given.
Tài liệu tham khảo
Heaney, 1999, Myelodysplasia, N Engl J Med, 340, 1649, 10.1056/NEJM199905273402107
Pellagatti, 2015, The molecular pathogenesis of the myelodysplastic syndromes, Eur J Haematol, 95, 3, 10.1111/ejh.12515
Tefferi, 2009, Myelodysplastic syndromes, N Engl J Med, 361, 1872, 10.1056/NEJMra0902908
Woll, 2014, Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo [published corrections appear in Cancer Cell. 2014;25(6):861 and Cancer Cell. 2015;27(4):603-5], Cancer Cell, 25, 794, 10.1016/j.ccr.2014.03.036
Sperling, 2017, The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia, Nat Rev Cancer, 17, 5, 10.1038/nrc.2016.112
Greenberg, 1997, International scoring system for evaluating prognosis in myelodysplastic syndromes, Blood, 89, 2079, 10.1182/blood.V89.6.2079
Greenberg, 2012, Revised international prognostic scoring system for myelodysplastic syndromes, Blood, 120, 2454, 10.1182/blood-2012-03-420489
Fenaux, 2013, How we treat lower-risk myelodysplastic syndromes, Blood, 121, 4280, 10.1182/blood-2013-02-453068
Gangat, 2016, Myelodysplastic syndromes: contemporary review and how we treat, Am J Hematol, 91, 76, 10.1002/ajh.24253
Ng, 2016, A 17-gene stemness score for rapid determination of risk in acute leukaemia, Nature, 540, 433, 10.1038/nature20598
Chen, 2019, Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level [published correction appears in Nat Med. 2019;25(3):529], Nat Med, 25, 103, 10.1038/s41591-018-0267-4
Dean, 2005, Tumour stem cells and drug resistance, Nat Rev Cancer, 5, 275, 10.1038/nrc1590
Gentles, 2010, Association of a leukemic stem cell gene expression signature with clinical outcomes in acute myeloid leukemia, JAMA, 304, 2706, 10.1001/jama.2010.1862
Eppert, 2011, Stem cell gene expression programs influence clinical outcome in human leukemia, Nat Med, 17, 1086, 10.1038/nm.2415
Gerstung, 2015, Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes, Nat Commun, 6, 5901, 10.1038/ncomms6901
Arber, 2016, The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia, Blood, 127, 2391, 10.1182/blood-2016-03-643544
Chou, 2011, TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics, Blood, 118, 3803, 10.1182/blood-2011-02-339747
Simons, 2013, Cytogenetic nomenclature: changes in the ISCN 2013 compared to the 2009 edition, Cytogenet Genome Res, 141, 1, 10.1159/000353118
Lin, 2014, IDH mutations are closely associated with mutations of DNMT3A, ASXL1 and SRSF2 in patients with myelodysplastic syndromes and are stable during disease evolution, Am J Hematol, 89, 137, 10.1002/ajh.23596
Lin, 2014, SF3B1 mutations in patients with myelodysplastic syndromes: the mutation is stable during disease evolution, Am J Hematol, 89, E109, 10.1002/ajh.23734
Hou, 2015, TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution, Blood Cancer J, 5, e331, 10.1038/bcj.2015.59
Hou, 2012, DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications, Blood, 119, 559, 10.1182/blood-2011-07-369934
Chou, 2011, Sensitive measurement of quantity dynamics of FLT3 internal tandem duplication at early time points provides prognostic information, Ann Oncol, 22, 696, 10.1093/annonc/mdq402
Shiah, 2002, Clinical and biological implications of partial tandem duplication of the MLL gene in acute myeloid leukemia without chromosomal abnormalities at 11q23, Leukemia, 16, 196, 10.1038/sj.leu.2402352
Lin, 2017, Higher HOPX expression is associated with distinct clinical and biological features and predicts poor prognosis in de novo acute myeloid leukemia, Haematologica, 102, 1044, 10.3324/haematol.2016.161257
Corces-Zimmerman, 2014, Pre-leukemic evolution of hematopoietic stem cells: the importance of early mutations in leukemogenesis, Leukemia, 28, 2276, 10.1038/leu.2014.211
Will, 2012, Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations, Blood, 120, 2076, 10.1182/blood-2011-12-399683
Shastri, 2017, Stem and progenitor cell alterations in myelodysplastic syndromes, Blood, 129, 1586, 10.1182/blood-2016-10-696062
Pang, 2013, Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes, Proc Natl Acad Sci USA, 110, 3011, 10.1073/pnas.1222861110
Walter, 2012, Clonal architecture of secondary acute myeloid leukemia, N Engl J Med, 366, 1090, 10.1056/NEJMoa1106968
Tehranchi, 2010, Persistent malignant stem cells in del(5q) myelodysplasia in remission, N Engl J Med, 363, 1025, 10.1056/NEJMoa0912228
Hope, 2004, Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity, Nat Immunol, 5, 738, 10.1038/ni1080
Bonnet, 1997, Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell, Nat Med, 3, 730, 10.1038/nm0797-730
Lapidot, 1994, A cell initiating human acute myeloid leukaemia after transplantation into SCID mice, Nature, 367, 645, 10.1038/367645a0
Meng, 2016, LAPTM4B: an oncogene in various solid tumors and its functions, Oncogene, 35, 6359, 10.1038/onc.2016.189
Xiao, 2017, LAPTM4B predicts axillary lymph node metastasis in breast cancer and promotes breast cancer cell aggressiveness in vitro, Cell Physiol Biochem, 41, 1072, 10.1159/000464115
Roy, 2018, Expression signature of lysosomal-associated transmembrane protein 4B in hepatitis C virus-induced hepatocellular carcinoma, Int J Biol Markers, 33, 283, 10.1177/1724600818773631
Dong, 2017, LAPTM4B-35 is a novel prognostic factor for glioblastoma [published correction appears in J Neurooncol. 2017;132(2):305-306], J Neurooncol, 132, 295, 10.1007/s11060-017-2369-0
Li, 2010, Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer, Nat Med, 16, 214, 10.1038/nm.2090
Ruiz-Lafuente, 2014, The gene expression response of chronic lymphocytic leukemia cells to IL-4 is specific, depends on ZAP-70 status and is differentially affected by an NFκB inhibitor, PLoS One, 9, e109533, 10.1371/journal.pone.0109533
Gao, 2017, BEX3 contributes to cisplatin chemoresistance in nasopharyngeal carcinoma, Cancer Med, 6, 439, 10.1002/cam4.982
Niavarani, 2016, A 4-gene expression score associated with high levels of Wilms Tumor-1 (WT1) expression is an adverse prognostic factor in acute myeloid leukaemia, Br J Haematol, 172, 401, 10.1111/bjh.13836
Wilson, 2002, Epithelial membrane proteins induce membrane blebbing and interact with the P2X7 receptor C terminus, J Biol Chem, 277, 34017, 10.1074/jbc.M205120200
Ben-Porath, 1996, Characterization of a tumor-associated gene, a member of a novel family of genes encoding membrane glycoproteins, Gene, 183, 69, 10.1016/S0378-1119(96)00475-1
Marvin, 1995, Identification and characterization of a novel squamous cell-associated gene related to PMP22, J Biol Chem, 270, 28910, 10.1074/jbc.270.48.28910
Ariës, 2014, EMP1, a novel poor prognostic factor in pediatric leukemia regulates prednisolone resistance, cell proliferation, migration and adhesion, Leukemia, 28, 1828, 10.1038/leu.2014.80
Sun, 2014, Epithelial membrane protein 1 negatively regulates cell growth and metastasis in colorectal carcinoma, World J Gastroenterol, 20, 4001, 10.3748/wjg.v20.i14.4001
Ahmat Amin, 2018, Epithelial membrane protein 1 promotes tumor metastasis by enhancing cell migration via copine-III and Rac1, Oncogene, 37, 5416, 10.1038/s41388-018-0286-0
Sun, 2014, Association of EMP1 with gastric carcinoma invasion, survival and prognosis, Int J Oncol, 45, 1091, 10.3892/ijo.2014.2488
Liu, 2017, The prognostic value of epithelial membrane protein 1 (EMP-1) in patients with laryngeal carcinoma, Med Sci Monit, 23, 3795, 10.12659/MSM.901161
Kim, 2016, Identification of carboxypeptidase X (CPX)-1 as a positive regulator of adipogenesis, FASEB J, 30, 2528, 10.1096/fj.201500107R
Kok, 2019, Gene expression signature that predicts early molecular response failure in chronic-phase CML patients on frontline imatinib, Blood Adv, 3, 1610, 10.1182/bloodadvances.2019000195
Kim, 2015, Carboxypeptidase X-1 (CPX-1) is a secreted collagen-binding glycoprotein, Biochem Biophys Res Commun, 468, 894, 10.1016/j.bbrc.2015.11.053
Raghavachari, 2012, A systematic comparison and evaluation of high density exon arrays and RNA-seq technology used to unravel the peripheral blood transcriptome of sickle cell disease, BMC Med Genomics, 5, 28, 10.1186/1755-8794-5-28
Zhang, 2015, Comparison of RNA-seq and microarray-based models for clinical endpoint prediction, Genome Biol, 16, 133, 10.1186/s13059-015-0694-1