IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL

Abstract

Relapse is the most common cause of treatment failure in pediatric acute lymphoblastic leukemia (ALL) and is often difficult to predict. To explore the prognostic impact of recurrent DNA copy number abnormalities on relapse, we performed high-resolution genomic profiling of 34 paired diagnosis and relapse ALL samples. Recurrent lesions detected at diagnosis, including PAX5, CDKN2A and EBF1, were frequently absent at relapse, indicating that they represent secondary events that may be absent in the relapse-prone therapy-resistant progenitor cell. In contrast, deletions and nonsense mutations in IKZF1 (IKAROS) were highly enriched and consistently preserved at the time of relapse. A targeted copy number screen in an unselected cohort of 131 precursor B-ALL cases, enrolled in the dexamethasone-based Dutch Childhood Oncology Group treatment protocol ALL9, revealed that IKZF1 deletions are significantly associated with poor relapse-free and overall survival rates. Separate analysis of ALL9-treatment subgroups revealed that non-high-risk (NHR) patients with IKZF1 deletions exhibited a B12-fold higher relative relapse rate than those without IKZF1 deletions. Consequently, IKZF1 deletion status allowed the prospective identification of 53% of the relapse-prone NHR-classified patients within this subgroup and, therefore, serves as one of the strongest predictors of relapse at the time of diagnosis with high potential for future risk stratification.

Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011

“…This may be due to the fact that we investigated a consecutive series of patients since similar findings were also reported in a previous population-based study. 18 It should be stressed, however, that the present results do not refute that specific subgroups, such as HeH and t(12;21), may harbor more changes at relapse. 16,17 Gene targets overrepresented in, or even unique for, relapse samples are most likely associated with treatment resistance and hence important to identify already at the time of diagnosis -perhaps being present only in a minor diagnostic subclone 40 -in order to adjust treatment accordingly.…”

“…In our series, deletions/pUPDs of IKZF1 were the only genetic change significantly associated with relapse in cases without any known risk-stratifying aberrations (Table 3), as also reported in a previous study. 21 Furthermore, we and others 13,18 show that all IKZF1 lesions at diagnosis are preserved at relapse, again supporting the poor prognostic impact of IKZF1 aberrations.…”

“…First, we investigated a population-based series, not focusing solely on high risk ALL, 4 T-ALL, 15 specific cytogenetic subgroups in BCP ALL, 16,17 or excluding some subgroups. 13 Also, none of our patients was lost to follow-up in contrast to several prior studies and for some of our cases the observation time was close to 20 years with a median follow-up of 10 years, whereas the maximum follow-up time has been 10 years or less in earlier studies, 14,17,18,20,21 (Figures 1 and 2). Furthermore, the SNP arrays used provide higher resolution (>1 M SNPs) compared with prior SNP array-based ALL studies (250K-500K), 4,[13][14][15][16][17][18] making it possible to delineate imbalances in greater detail and to identify previously unknown gene targets, as exemplified below.…”

“…The transcription factor IKZF1 is essential for B-cell development, with loss of IKZF1 leading to arrest of lymphoid differentiation. 46,47 IKZF1 abnormalities were initially associated with an inferior outcome of high risk BCP ALL only, 21,48 but the present data and two previous studies 18,20 clearly show that IKZF1 aberrations also predict poor outcome in the standard and intermediate risk groups. In our series, deletions/pUPDs of IKZF1 were the only genetic change significantly associated with relapse in cases without any known risk-stratifying aberrations (Table 3), as also reported in a previous study.…”

“…4,[9][10][11][12]16,17 In addition, high-resolution genomic profiling has identified genes, for example CDKN2A, ETV6, IKZF1, and EBF1, that are more frequently deleted in samples from patients who subsequently relapse than in samples from those remaining in fist complete remission (CR1). 4,13,14,18 However, whether these deletions serve as independent prognostic markers is still unclear. 13,14,18,19 4 In the present study, SNP array analyses were performed on diagnostic, CR1, relapse (R), and induction failure (IF) samples from pediatric ALL patients to identify copy number aberrations and uniparental isodisomies (UPDs) associated with R/IF.…”