IKZF1 Deletion in Acute Lymphoblastic Leukemia: A Single-Center Experience in Thailand

Suchada Sommaluan; Adcharee Kongruang; Takol  Chareonsirisuthigul; Budsaba Rerkamnuaychoke; Pimjai  Niparuck; Pongpak Pongphitcha; Samart Pakakasama; Nittaya Limsuwanachot; Teerapong Siriboonpiputtana

Authors

Suchada Sommaluan Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Adcharee Kongruang Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Takol Chareonsirisuthigul Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Budsaba Rerkamnuaychoke Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Pimjai Niparuck Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Pongpak Pongphitcha Department of Pediatric, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Samart Pakakasama Department of Pediatric, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Nittaya Limsuwanachot Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Teerapong Siriboonpiputtana Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

Keywords:

IKZF1 deletion, B-cell precursor acute lymphoblastic leukemia (BCP-ALL), multiplex ligation-dependent probe amplification (MLPA), BCR::ABL1 p190 positive

Abstract

Genetic deletions of IKZF1 have been extensively studied and linked to unfavorable prognosis in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, the distribution and prognostic significance of restricted IKZF1 deletion in BCP-ALL is unclear. This study aimed to analyze the distribution, clinical impact, and overall survival of IKZF1 deletions in both adult and childhood BCP-ALL. Sixty-two genomic DNA samples isolated from patients with BCP-ALL were analyzed using the MLPA method. Gene deletions were detected in 64.5% of cases. The deletion of CDKN2A was the most frequent genetic alteration (50.0%) in the tested samples, followed by the deletion of IKZF1 (47.5%) and deletion of CDKN2B (45.0%). Gene duplications were detected in 32.3% of cases. The duplications of CSF2RA and IL3RA were the most frequent genetic alteration (75.0%) in the tested samples, followed by duplications of SHOX-AREA-Down, CRLF2, P2RY8 (70.0%) and duplications of PAX5 (30.0%). 42.1% detected deletion of IKZF1 with t(9;22) and BCR::ABL1 p190 positive. In addition, the impact of IKZF1 deletions had shorter overall survival (OS) compared to those without IKZF1 deletions (p = 0.047), and patients with both IKZF1 and BCR::ABL1 p190 deletions had significantly poorer outcomes, with shorter eight-year overall survival (OS) (p = 0.0234). In summary, we revealed the association between IKZF1 deletions and survival outcomes of patients with BCP-ALL. Our data demonstrated that patients with IKZF1 deletion have shorter OS than those without IKZF1 deletion. Furthermore, the combination of BCR::ABL1 positivity and IKZF1 deletion, showing a poorer prognosis, as indicated by shorter OS, compared to patients without BCR::ABL1 or IKZF1 detection.

References

Iacobucci I, Mullighan CG. Genetic basis of acute lymphoblastic leukemia. J Clin Oncol. 2017;35(9):975–83.

Pui C-H, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet. 2008;371(9617):1030–43.

Ko RH, Ji L, Barnette P, Bostrom B, Hutchinson R, Raetz E, et al. Outcome of patients treated for relapsed or refractory acute lymphoblastic leukemia: A Therapeutic Advances in Childhood Leukemia Consortium study. J Clin Oncol. 2010;28(4):648–54.

DeAngelo DJ, Jabbour E, Advani A. Recent advances in managing acute lymphoblastic leukemia. Am Soc Clin Oncol Educ Book. 2020;40:330–42.

Joshi I, Yoshida T, Jena N, Qi X, Zhang J, Van Etten RA, et al. Loss of Ikaros DNA-binding function confers integrin-dependent survival on pre-B cells and progression to acute lymphoblastic leukemia. Nat Immunol. 2014;15(3):294–304.

Mullighan CG, Su X, Zhang J, Radtke I, Phillips LAA, Miller CB, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470–80.

Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453(7191):110–4.

Kastner P, Dupuis A, Gaub M, Herbrecht R, Lutz P, Chan S. Function of Ikaros as a tumor suppressor in B cell acute lymphoblastic leukemia. Am J Blood Res. 2013;3(1):1–13.

Marke R, van Leeuwen FN, Scheijen B. The many faces of IKZF1 in B-cell precursor acute lymphoblastic leukemia. Haematologica. 2018;103(4):565–74.

Martinelli G, Iacobucci I, Storlazzi CT, Vignetti M, Paoloni F, Cilloni D, 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(31):5202–7.

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: on behalf of Gruppo Italiano Malattie Ematologiche dell’Adulto Acute Leukemia Working Party (GIMEMA AL WP). Blood. 2009;114(10):2159–67.

Stanulla M, Cavé H, Moorman AV. IKZF1 deletions in pediatric acute lymphoblastic leukemia: still a poor prognostic marker? Blood. 2020;135(4):252–60.

Lin S, Liao N, Li X, Yang L, He Y-Y, Tang Y-L, et al. Prognosis of pediatric BCP-ALL with IKZF1 deletions and impact of intensive chemotherapy: Results of SCCLG-2016 study. Eur J Haematol. 2024;113(3):357–70.

Cui L, Gao C, Wang CJ, Zhao XX, Li WJ, Li ZG, et al. Combined analysis of IKZF1 deletions and CRLF2 expression on prognostic impact in pediatric B-cell precursor acute lymphoblastic leukemia. Leuk Lymphoma. 2021;62(2):410-8.

Dorge P, Meissner B, Zimmermann M, Moricke A, Schrauder A, Bouquin JP, et al. IKZF1 deletion is an independent predictor of outcome in pediatric acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol. Haematologica. 2013;98(3):428-32.

Tokunaga K, Yamaguchi S, Iwanaga E, Nanri T, Shimomura T, Suzushima H, et al. High frequency of IKZF1 genetic alterations in adult patients with B-cell acute lymphoblastic leukemia. Eur J Haematol. 2013;91(3):201-8.

Patel S, Mason CC, Glenn MJ, Paxton CN, South ST, Cessna MH, et al. Genomic analysis of adult B-ALL identifies potential markers of shorter survival. Leuk Res. 2017;56:44-51.

Krentz S, Hof J, Mendioroz A, Vaggopoulou R, Dorge P, Lottaz C, et al. Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia. Leukemia. 2013;27(2):295-304.

Kathiravan M, Singh M, Bhatia P, Trehan A, Varma N, Sachdeva MS, et al. Deletion of CDKN2A/B is associated with inferior relapse free survival in pediatric B cell acute lymphoblastic leukemia. Leuk Lymphoma. 2019;60(2):433-41.

Xu N, Li YL, Zhou X, Cao R, Li H, Lu QS, et al. CDKN2 Gene Deletion as Poor Prognosis Predictor Involved in the Progression of Adult B-Lineage Acute Lymphoblastic Leukemia Patients. J Cancer. 2015;6(11):1114-20.

Moorman AV, Barretta E, Butler ER, Ward EJ, Twentyman K, Kirkwood AA, et al. Prognostic impact of chromosomal abnormalities and copy number alterations in adult B-cell precursor acute lymphoblastic leukaemia: a UKALL14 study. Leukemia. 2022;36(3):625-36.

Iacobucci I, Lonetti A, Paoloni F, Papayannidis C, Ferrari A, Storlazzi CT, et al. The PAX5 gene is frequently rearranged in BCR-ABL1-positive acute lymphoblastic leukemia but is not associated with outcome. A report on behalf of the GIMEMA Acute Leukemia Working Party. Haematologica. 2010;95(10):1683-90.

Fedullo AL, Messina M, Elia L, Piciocchi A, Gianfelici V, Lauretti A, et al. Prognostic implications of additional genomic lesions in adult Philadelphia chromosome-positive acute lymphoblastic leukemia. Haematologica. 2019;104(2):312-8.

van der Veer A, Zaliova M, Mottadelli F, De Lorenzo P, Te Kronnie G, Harrison CJ, et al. IKZF1 status as a prognostic feature in BCR-ABL1-positive childhood ALL. Blood. 2014;123(11):1691-8.

van Outersterp I, Boer JM, van de Ven C, Reichert CEJ, Boeree A, Kruisinga B, et al. Tyrosine kinase inhibitor resistance in de novo BCR::ABL1-positive BCP-ALL beyond kinase domain mutations. Blood Adv. 2024;8(8):1835-45.

van der Veer A, Waanders E, Pieters R, Willemse ME, Van Reijmersdal SV, Russell LJ, et al. Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL. Blood. 2013;122(15):2622-9.

Palmi C, Bresolin S, Junk S, Fazio G, Silvestri D, Zaliova M, et al. Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia. Hemasphere. 2023;7(6):e892.