Heterogeneity of IKZF1 genomic alterations and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia

Ruth W. Wang'ondu, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Emily Ashcraft, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
Ti-Cheng Chang, Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.
Kathryn G. Roberts, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Samuel W. Brady, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Yiping Fan, Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.
William Evans, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Mary V. Relling, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Kristine R. Crews, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Jun Yang, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Wenjian Yang, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Stanley Pounds, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
Gang Wu, Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.
Meenakshi Devidas, Department of Global Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, TN, USA.
Kelly Maloney, Department of Pediatrics and Children's Hospital Colorado, University of Colorado, Aurora, CO, USA.
Leonard Mattano, HARP Pharma Consulting, Mystic, CT, USA.
Reuven J. Schore, Division of Oncology, Center for Cancer and Blood Disorders, Children's National Hospital, Washington DC, WA, USA.
Anne Angiolillo, Servier Pharmaceuticals, Boston, MA, USA.
Eric Larsen, Department of Pediatrics, Maine Children's Cancer Program, Scarborough, ME, USA.
Wanda Salzer, Uniformed Services University, School of Medicine, Bethesda, MD, USA.
Michael J. Burke, Division of Pediatric Hematology-Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
Mignon L. Loh, Ben Towne Center for Childhood Cancer Research and the Department of Pediatrics, Seattle Children's Hospital, University of Washington, and the Fred Hutchinson Cancer Center, Seattle, WA, USA.
Sima Jeha, Department of Global Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, TN, USA.
Ching-Hon Pui, Department of Global Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, TN, USA.
Hiroto Inaba, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Cheng Cheng, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
Charles G. Mullighan, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA. charles.mullighan@stjude.org.

Document Type

Journal Article

Publication Date

5-13-2025

Journal

Leukemia

DOI

10.1038/s41375-025-02633-3

Abstract

Genomic alterations of IKZF1 are common and associated with adverse clinical features in B-progenitor acute lymphoblastic leukemia (B-ALL). The relationship between the type of IKZF1 alteration, B-ALL genomic subtype and outcome are incompletely understood. B-ALL subtype and genomic alterations were determined using transcriptome and genomic sequencing, and SNP microarray analysis in 688 pediatric patients with B-ALL in the St. Jude Total Therapy XV and 16 studies. IKZF1 alterations were identified in 115 (16.7%) patients, most commonly in BCR::ABL1 (78%) and CRLF2-rearranged, BCR::ABL1-like B-ALL (70%). These alterations were associated with 5-year cumulative incidence of relapse (CIR) of 14.8 ± 3.3% compared to 5.0 ± 0.9% for patients without any IKZF1 alteration (P < 0.0001). In separate multivariable analyses adjusting for genetic subtype groups and other factors, IKZF1 deletions of exons 4-7 (P = 0.0002), genomic IKZF1 with any IKZF1 deletion (P = 0.006) or with focal IKZF1 deletion (P = 0.0007), and unfavorable genomic subtypes (P < 0.005) were independently adverse prognostic factors. Associations of genomic IKZF1 and exon 4-7 deletions with adverse outcomes were confirmed in an independent cohort. The type of IKZF1 alteration, together with the subtype, are informative for risk stratification and to predict response in patients with B-ALL.

Department

Pediatrics

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