2016, Number 4
<< Back
Rev Invest Clin 2016; 68 (4)
IKAROS Gene Deleted B-Cell Acute Lymphoblastic Leukemia in Mexican Mestizos: Observations in Seven Patients and a Short Review of the Literature
Ruiz-Delgado GJ, Cantero-Fortiz Y, León-Peña AA, León-González M, Nuñez-Cortés AK, Ruiz-Argüelles GJ
Language: English
References: 33
Page: 210-214
PDF size: 77.19 Kb.
ABSTRACT
Background: In B-cell acute lymphoblastic leukemia, one of the most frequent cytogenetic alterations is the presence of the
Philadelphia chromosome. Recently, newly identified genetic alterations have been studied, among them the
IKZF1 deletion.
IKZF1
encodes
IKAROS, a zinc finger protein that plays an important role in hematopoiesis involving the regulation process of adhesion,
cellular migration, and as a tumor suppressor.
Objective: We aimed to study the impact of IKAROS deletion in the evolution and
prognosis of B-cell acute lymphoblastic leukemia.
Materials and Methods: At a single center we prospectively studied patients
diagnosed with B-cell acute lymphoblastic leukemia and screened for
IKZF1 deletion using the multiplex ligation-dependent probe
amplification method. We did a descriptive analysis of patients positive for the
IKZF1 deletion to determine its impact on the
evolution of the disease and survival rate.
Results: Between 2010 and 2015, 16 Mexican mestizo patients with B-cell acute
lymphoblastic leukemia were prospectively screened for
IKZF1 deletion; seven (43%) were positive and were included for further
analysis. The age range of patients was 13-60 years; six were males and one female. All cases had type B acute lymphoblastic
leukemia. Of the seven patients, two died, three were lost to follow-up, and two continue in complete remission with treatment.
Results are worse than those in a group of patients with non-mutated
IKAROS B-cell acute lymphoblastic leukemia previously
studied in our center.
Conclusions: Although this is a small sample, the presence of
IKAROS deletion in acute lymphoblastic
leukemia patients could represent a poor-prognosis marker and was probably related to therapy failure. It is also possible that
this variant of leukemia may be more prevalent in Mexico. More studies are needed to define the role of
IKZF1 deletion in acute
lymphoblastic leukemia and the real prevalence of the disease in different populations.
REFERENCES
Faderl S, Kantarjian HM, Talpaz M, Estrov Z. Clinical significance of cytogenetic abnormalities in adult acute lymphoblastic leukemia. Blood. 1998;91:3995-4019.
Pui CH, Robinson LL, Look AT. Acute lymphoblastic leukemia. Lancet. 2008;371:1030-43.
Bleyer A, O’Leary M, Barr R, Ries LAG. Cancer epidemiology in older adolescents and young adults 15 to 29 years of age, including SEER incidence and survival: 1975-2000. National Cancer Institute, NIH Pub. No. 06-5767. Bethesda, MD. 2006.
Ribera JM, Tormo M, Ortega JJ. [Acute lymphoblastic leukemia in adolescents and adults.] Med Clin Monogr (Barc). 2007; 129:36-9.
Liu-Dumlao T, Kantarjian H, Thomas DA, O’Brien S, Ravandi F. Philadelphia-positive acute lymphoblastic leukemia: current treatment options. Curr Oncol Rep. 2012;14:387-94.
Martinelli G, Iacobucci I, Storlazzi CT, et. al. IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse: A GIMEMA AL WP report. J Clin Oncol. 2009;27:5202-7.
Davis KL. Ikaros: master of hematopoiesis, agent of leukemia. Ther Adv Hematol. 2011;2:359-68.
Bottardi S, Ross J, Bourgoin V, et al. Ikaros and GATA-1 combinatorial effect is required for silencing of human gamma-globin genes. Mol Cell Biol. 2009;29:1526-37.
Winandy S, Wu P, Georgopoulos K. A dominant mutation in the ikaros gene leads to rapid development of leukemia and lymphoma. Cell. 1995;83:289-99.
Payne KJ, Dovat S. Ikaros and tumor suppression in acute lymphoblastic leukemia. Crit Rev Oncog. 2011;16:3-12.
Kathrein KL, Chari S, Winandy S. Ikaros directly represses the Notch target gene Hes 1 in a leukemia T cell line. Implications for CD4 regulation. J Biol Chem. 2008;283:10476-84.
Ma S, Pathak S, Mandal M, Trinh L, Clark MR, Lu R. Ikaros and Aiolos inhibit Pre B-cell proliferation by directly suppressing c-Myc expression. Mol Cell Biol. 2010;30:4149-58.
Gómez-del Arco P, Maki K , Georgopoulos K. Phosphorylation controls Ikaros ability to negatively regulate the G(1).S transition. Mol Cell Biol. 2004;24:2797-807.
Kano G, Morimoto A, Takanashi M, Hibi S, Sugimoto T, Inaba T, et al. Ikaros dominant negative isoform (Ik6) induces IL-3 independent survival of murine pro B lymphocytes by activating JAK-STAT and up-regulating Bcl-xl levels. Leuk Lymphoma. 2008;49:965-73.
Song C, Gowda C, Pan X, et al. Targeting casein kinase ll restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia. Blood. 2015;126:1813-22.
Stuppia L, Antonucci I, Palka G, Gatta V. Use of the MLPA assay in the molecular diagnosis of gene copy number alterations in human genetic diseases. Int J Mol Sci. 2012;13:3245-76.
Ruiz-Delgado GJ, Macías-Gallardo J, Lutz-Presno J, Montes-Montiel M, Ruiz-Argüelles GJ. Outcome of adults with acute lymphoblastic leukemia treated with a pediatric-inspired therapy: A single institution experience. Leuk Lymphoma. 2011;52: 314-6.
Molnár A, Wu P, Largespada DA, et al. The Ikaros gene encodes a family of lymphocyte-restricted zinc finger DNA binding proteins, highly conserved in human and mouse. J Immunol. 1996; 156:585-92.
Koipally J, Heller EJ, Seavitt JR, Georgopoulos K. Unconventional potentiation of gene expression by Ikaros. J Biol Chem. 2002; 277:13007-15.
Yoshida T, Georgopoulos K. Ikaros fingers on lymphocyte differentiation. Int J Hematol. 2014;100:220-9.
Dijon M, Bardin F, Murati A, Batoz M, Chabannon C, Tonnelle C. The role of Ikaros in human erythroid differentiation. Blood. 2008;111:1138-46.
O´Neill DW, Schoetz SS, Lopez RA, et al. An Ikaros -containing chromatin-remodeling complex in adult-type erythroid cells. Mol Cell Biol. 2000;20:7572-82.
Molnár A, Geogopoulos K. The Ikaros gene encodes a family of functionally diverse zinc finger DNA- binding proteins. Mol Cell Biol. 1994;14:8292-303.
Sun L, Liu A, Georgopolos K. Zinc finger-mediated protein interactions modulate Ikaros activity, a molecular control of lymphocyte development. EMBO J. 1996;15:5358-69.
Schwickert TA, Tagoh H, Gültekin S, et al. Stage-specific control of early B cell development by the transcription factor Ikaros. Nat Immunol. 2014;15:283-93.
Bottardi S, Mavoungou L, Pak H, et al. The IKAROS Interaction with a complex including chromatin remodeling and transcription elongation activities is required for hematopoiesis. Plos Genet. 2014;10:e1004827.
Tokunaga K, Yamaguchi S, Iwanaga E, et al. High frequency of IKZF1 genetic alterations in adult patients with B-cell acute lymphoblastic leukemia. Eur J Haematol. 2013;91: 201-8.
Cytogenetic abnormalities in adult acute lymphoblastic leukemia: correlations with hematologic findings outcome. A collaborative study of The Group Français de Cytogénétique Hématologique. Blood. 1996;87:3135-42.
Preti HA, O´Brien S, Giralt S, Beran M, Pierce S, Kantarjian HM. Philadelphia-chromosome-positive adult acute lymphocytic leukemia: characteristics, treatment results, and prognosis in 41 patients. Am J Med. 1994;97:60-5.
Mulligham CG, Su X, Zhang J, et al. Children´s oncology group. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360:470-80.
Eguigueren JM, Schell MJ, Crist WM, Kungel K, Rivera GK. Complications and outcome in childhood acute lymphoblastic leukemia. Blood. 1992;79:871-5.
Pui CH, Pei D, Sandlund JT, et al. Long-term results of St. Jude total therapy studies 11, 12, 13A, 13B and 14 for childhood acute lymphoblastic leukemia. Leukemia. 2010;24:371-82.
Barret AJ, Horowitz MM, Ash RC, et al. Bone marrow transplantation for Philadelphia chromosome- positive acute lymphoblastic leukemia. Blood. 1992;79:3067-7