Abstract Objective To analyze the isoforms of IKAROS in the bone marrow samples from children with acute B-lineage lymphoblastic leukemia (B-ALL) and to investigate the relationship between frequency of dominant-negative (DN) IKAROS isoforms and prognosis of B-ALL, and to preliminarily study the relevant mechanism. Methods A total of 137 children with newly diagnosed B-ALL, who sequentially entered the Department of Hematology and Oncology, Shanghai Children’s Medical Center between January 2005 and September 2010, were included in the study. Nest-PCR, Sanger sequencing, and TA cloning were used to analyze the expression of IKAROS isoforms in these children. The relationship between frequency of DN IKAROS isoforms and prognosis of B-ALL was investigated. Results Of the 137 children with newly diagnosed B-ALL, 16 had expression of IK6, 14 had expression of IK4, and 2 had expression of IK7. There was significant difference in 2.5-year event-free survival between the cohorts of DN IKAROS and non-DN IKAROS (P=0.01). Analysis of the 10 paired of diagnosis/relapse samples from 10 patients with recurrence showed that 8 of 10 paired diagnosis and relapse samples had inconsistent expression of IKAROS isoforms. The rate of IK6 expression in relapse samples from 21 relapse ALL patients was significantly higher than in the 137 children with newly diagnosed ALL (62% vs 12%, P<0.01). Conclusions Expression of DN IKAROS isoforms can be a poor prognostic factor in B-ALL and is closely associated with recurrence of B-ALL.
Nietfeld W, Meyerhans A. Cloning and sequencing of Hik-1, a cDNA encoding a human homologue of mouse IKAROS/LyF-1[J]. Immunol Lett, 1996, 49(1-2):139-141.
[2]
Molnar A, Wu P, Largespada DA, Vortkamp A, Scherer S, Copeland NG, et al. The IKAROS gene encodes a family of lymphocyte-resticted zinc finger DNA binding proteins, highly conserved on human and mouse[J]. J Immun, 1996, 156(2):585-592.
[3]
Georgopoulos K, Moore DD, Derfler B. Ikaros, an early lymphoid-sepcific transcription factor and a putative mediator for T cell commitment[J]. Science, 1992, 258(5083): 808-812.
[4]
NaKase K, Ishimaru F, Avitahl N, Dansako H, Matsuo K, Fujii K, et al. Dominant negative isoform of the IKAROSgene in patients with adult B-ALL acute lymphoblastic leukemia[J]. Cancer Res, 2000, 60(15): 4062-4065.
[5]
Sun L, Crotty ML, Sensel M, Sather H, Navara C, Nachman J, et al. Expression of dominant-negative isoforms in T-cell acute lymphoblastic leukemia[J]. Cancer Res, 1999, 5(8): 2112-2120.
[6]
Yagi T, Hibi S, Takanshi M, Kano G, Tabata Y, Imamura T, et al. High frequency of IKAROS isoform 6expression in acute myelomonocytic and monocyticleukemia: implications for upregulation of the antiapoptotic protein BCR-XL in leukemogenesis[J]. 2002, 99(4): 1350-1355.
[7]
Iacobucci I, Storlazzi CT, Cilloni D, Lonetti A, Ottaviani E, Soverini S, et al. Identification and molecular characterization of recurrent genomic deletions on 7p12 in the IKZF1 gene in a large cohort of BCR-ABL1-positive acute lymphoblastic leukemia patients[J]. Blood, 2009, 114(10): 2159-2167.
[8]
Kuiper RP, Waanders E, van der Velden VH, van Reijmersdal SV, Venkatachalam R, Scheijen B, et al. IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL[J]. Leukemia, 2010, 24(7): 1258-1264.
[9]
Den Boer ML, van Slegtenhorst M, De Menezes RX, Cheok MH, Buijs-Gladdines JG, Peters ST, et al. A subtype of childhood acute lymphoblastic leukemia with poor treatment outcome: a genome-wide classification study[J]. Lancet Oncol, 2009, 10(2): 125-134.
[10]
Trevino LR, Yang W, French D, Hunger SP, Carroll WL, Devidas M, et al. Germline genomic variants associated with childhood acute lymphoblastic leukemia[J]. Nat Genet, 2009, 41(9): 1001-1005.
[11]
Silverman LB, Steven KE, O'Brien JE, Asselin BL, Barr RD, Clavell L, et al. Long-term results of Dana-Farber CancerInstitute ALLconsortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985-2000)[J]. Leukemia, 2010, 24(2): 320-334.
[12]
Gaynon PS, Angiolill AL, Carroll WL, Nachman JB, Trigg ME, Sather HN, et al. Long-term results of the children's cancer group studies for childhood acute lymphoblastic leukemia 1983-2002: a children's Oncology group report[J]. Leukemia, 2010, 24(2): 285-297.
[13]
Yang JJ, Bhojwani D, Yang W, Cai X, Stocco G, Crews K, et al. Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia[J]. Blood, 2008, 112(10): 4178-4183.
[14]
Zhou F, Mei H, Jin R, Li X, Chen X. Expression of Ikaros isoform 6 in Chinese children with acute lymphoblastic leukemia[J]. J Pediatr Hematol Oncol, 2011, 33(6): 429-432.
[15]
Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, et al. BCR-ABL lymphoblastic leukemia is chara-cterized by the deletion of ikaros[J]. Nature, 2008, 453(7191): 110-114.
