Clonal heterogeneity and rates of specific chromosome gains are risk predictors in childhood high‐hyperdiploid B‐cell acute lymphoblastic leukemia

Abstract

B‐cell acute lymphoblastic leukemia (B‐ALL) is the commonest childhood cancer. High hyperdiploidy (HHD) identifies the most frequent cytogenetic subgroup in childhood B‐ALL. Although hyperdiploidy represents an important prognostic factor in childhood B‐ALL, the specific chromosome gains with prognostic value in HHD‐B‐ALL remain controversial, and the current knowledge about the hierarchy of chromosome gains, clonal heterogeneity and chromosomal instability in HHD‐B‐ALL remains very limited. We applied automated sequential‐iFISH coupled with single‐cell computational modeling to identify the specific chromosomal gains of the eight typically gained chromosomes in a large cohort of 72 primary diagnostic (DX, n = 62) and matched relapse (REL, n = 10) samples from HHD‐B‐ALL patients with either favorable or unfavorable clinical outcome in order to characterize the clonal heterogeneity, specific chromosome gains and clonal evolution. Our data show a high degree of clonal heterogeneity and a hierarchical order of chromosome gains in DX samples of HHD‐B‐ALL. The rates of specific chromosome gains and clonal heterogeneity found in DX samples differ between HHD‐B‐ALL patients with favorable or unfavorable clinical outcome. In fact, our comprehensive analyses at DX using a computationally defined risk predictor revealed low levels of trisomies +18+10 and low levels of clonal heterogeneity as robust relapse risk factors in minimal residual disease (MRD)‐negative childhood HHD‐B‐ALL patients: relapse‐free survival beyond 5 years: 22.1% versus 87.9%, P < 0.0001 and 33.3% versus 80%, P < 0.0001, respectively. Moreover, longitudinal analysis of matched DX‐REL HHD‐B‐ALL samples revealed distinct patterns of clonal evolution at relapse. Our study offers a reliable prognostic sub‐stratification of pediatric MRD‐negative HHD‐B‐ALL patients.

Overview on Aneuploidy in Childhood B-Cell Acute Lymphoblastic Leukemia

“…Similarly, favorable patient outcomes can be seen with high +18 hyperdiploidy, while chromosome 5 gains are likely associated with a poorer prognosis [40,57,[74][75][76]. In addition, this was confirmed by the results of Ramos-Muntada et al, in whose study the percentage of trisomy 18 in diagnostic samples was significantly higher in patients with complete remission than in patients with relapse [16].…”

“…The most characteristic subtypes with aneuploidy are B-cell ALL with hypodiploidy and hyperdiploidy, while aneuploidy in T-cell ALL is much less described. T-ALL occurs more frequently in adults than in children and the WHO-HAEM-5 defines only a subtype of early T-cell precursor lymphoblastic leukemia [8,9,[13][14][15][16][17][18]. The only aneuploidy that happens often among T-ALL cases is near-tetraploidy-in the study described by Ceppi et al, 1.4% of patients were diagnosed with near-tetraploid T-ALL [11,19].…”

The Eμ-Ret mouse is a novel model of hyperdiploid B-cell acute lymphoblastic leukemia

“…HD-ALL is characterized by non-random chromosomal gains, with combinations of chromosomes X, 4, 6, 10, 14, 17, 18, and 21, mostly in the form of trisomies, accounting for 75% of the changes [ 3 , 4 ]. Chromosomal content is associated with prognosis and the pattern of gains and losses is increasingly used for risk stratification [ 5 , 6 ]. In contrast to other aneuploid malignancies, the abnormal karyotype is relatively stable through HD-ALL progression.…”

Chromosomal instability in aneuploid acute lymphoblastic leukemia associates with disease progression

“…The presence of CIN and its contribution to aneuploid cB-ALL progression is largely unknown due to the lack of preclinical models to study actively dividing cells. Accordingly, studies of CIN in cB-ALL are limited to the characterization of chromosomal copy-number heterogeneity (chr-CNH) in primary cB-ALL samples and remain controversial due to the different techniques used to assess karyotype variability (Alpar et al, 2014 ; Heerema et al, 2007 ; Paulsson et al, 2010 ; Ramos-Muntada et al, 2022 ; Talamo et al, 2010 ). Importantly, although increased rates of chromosome mis-segregation have been shown in actively dividing HeH-B-ALL cells in patient-derived xenograft (PDX) models (Molina et al, 2020 ), they are vastly unexplored in other clinically relevant aneuploid subtypes, such as HoL- and NH-B-ALL.…”