Deletion ofIKZF1and Prognosis in Acute Lymphoblastic Leukemia

Abstract

Background Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined. Methods We studied a cohort of 221 children with high-risk B-cell–progenitor ALL with the use of single-nucleotide–polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1–positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell–progenitor ALL. Results More than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell–lineage genes, and it was similar to the signature of BCR-ABL1–positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion. Conclusions Genetic alteration of IKZF1 is associated with a very poor outcome in B-cell–progenitor ALL.

Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T‐cell acute lymphoblastic leukemia

“…Although PAX5 alterations are the most frequent genetic abnormality in precursor B-cell ALL [40], the loss of PAX5 is not associated with poor outcomes, possibly because of a lack of deregulation in stem cell-associated genes [41]. In contrast, deletion or sequence mutation of the IKZF1 gene, encoding the early lymphoid transcription factor Ikaros, increases the risk of treatment failure [42][43][44][45]. It appears that when leukemias occur in the earlier phases of lymphocyte development, the prognosis is poorer for childhood ALL, irrespective of whether it is B-or T-cell ALL.…”

“…Similar results have been obtained for progenitor B-cell ALL. IKZF1 deletions have recently been identified as a poor prognostic marker for relapse in progenitor B-cell ALL [42]. Interestingly, its alterations are also the top three frequently encountered new genetic alterations in relapsed samples.…”

Prognostic impact of IKZF1 deletions in association with vincristine–dexamethasone pulses during maintenance treatment of childhood acute lymphoblastic leukemia on trial ALL-BFM 95

“…1,2 In several studies, deletions of IKZF1-encoding IKAROS, a transcription factor important for lymphoid development and differentiation-have been associated with a poor treatment outcome in precursor B cell ALL. [3][4][5] Deletions of IKZF1 are observed in 10-15% of pediatric ALLs and affect either the entire IKZF1 gene or appear as focal deletions. [3][4][5] The most common of the latter ones (Δ4-7) includes the DNA-binding region and results in a dominant-negative isoform (Ik6), impairing cell differentiation in CD34+ lymphoid progenitor cells.…”

“…[3][4][5] Deletions of IKZF1 are observed in 10-15% of pediatric ALLs and affect either the entire IKZF1 gene or appear as focal deletions. [3][4][5] The most common of the latter ones (Δ4-7) includes the DNA-binding region and results in a dominant-negative isoform (Ik6), impairing cell differentiation in CD34+ lymphoid progenitor cells. [3][4][5] Recently, Clappier et al 6 from the EORTC Study Group suggested that patients with IKZF1-deleted ALL and intermediate-risk features-so-called average-risk (AR) patientstreated on the BFM-based EORTC protocol 58951 may benefit from intensification of conventional maintenance therapy by application of vincristine-glucocorticoid pulses.…”

“…[3][4][5] The most common of the latter ones (Δ4-7) includes the DNA-binding region and results in a dominant-negative isoform (Ik6), impairing cell differentiation in CD34+ lymphoid progenitor cells. [3][4][5] Recently, Clappier et al 6 from the EORTC Study Group suggested that patients with IKZF1-deleted ALL and intermediate-risk features-so-called average-risk (AR) patientstreated on the BFM-based EORTC protocol 58951 may benefit from intensification of conventional maintenance therapy by application of vincristine-glucocorticoid pulses. We previously reported that on ALL-BFM protocols IKZF1 status exerts additive value as a prognostic factor, especially in the intermediate-risk group, in which still the majority of relapses occur.…”