High hyperdiploid acute lymphoblastic leukemia in adults shows clonal heterogeneity and chromosomal instability at diagnosis and during the course of the disease

Talamo, Anna; Marazzi, Alfio; Rovó, Alicia; Schanz, Urs; Thewis, André; Chalandon, Yves; Jotterand, Martine

doi:10.1007/s00277-011-1317-x

Cited by 3 publications

(3 citation statements)

References 10 publications

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“…Earlier studies have reported contradictory data on the presence of clonal heterogeneity in HHD‐B‐ALL which depend on the methodology of analysis used [9,23,25,41]. Consistent with our data, clonal heterogeneity was observed by iFISH [23–25], spectral‐karyotyping [42], single‐cell next‐generation sequencing [43] and by cell division studies directly assessing chromosome segregation in primary leukemic blasts [21]. Our results reinforce that conventional karyotyping fails to reflect the actual clonal heterogeneity in HHD‐B‐ALL patients, suggesting that clonal selection seen in conventional karyotyping analysis likely arises from the cell culture needed for karyotyping, which may mask the actual clonal composition of HHD‐B‐ALL samples.…”

Section: Discussionsupporting

confidence: 88%

“…Thus, fluorescence in situ hybridization on interphase nuclei (iFISH) in combination with conventional cytogenetics has proved to be useful for the accurate detection of chromosomal gains, as iFISH does not require dividing cells and it can detect hidden clones and mosaicism within the samples [ 22 ]. Indeed, the use of iFISH by independent groups has revealed high levels of clonal heterogeneity in HHD‐B‐ALL samples [ 23 , 24 , 25 ], with multiple subclones containing different combinations of chromosomal gains in individual cells, suggesting chromosomal instability (CIN) within HHD‐B‐ALL. Notably, sequential iFISH analysis (seq‐iFISH), which permits identification of the eight typically gained chromosomes in HHD‐B‐ALL, showed changes in chromosome number to be hierarchical with sequential chromosomal gains, rather than losses, retained from lower to higher MNs [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…57 These data support previous studies showing the presence of cytogenetically different subclones in HyperD-ALL. [58][59][60][61] Mechanistically, HyperD-ALL primary blasts and cell lines did not show abnormalities in bipolar spindle and kinetochore formation. However, they displayed important chromosome-structure and -function defects, a major mechanism regulating chromosome segregation that is essential for maintaining the genomic integrity of cells.…”

Section: Discussionmentioning

confidence: 91%

Impaired Condensin Complex and Aurora B kinase underlie mitotic and chromosomal defects in hyperdiploid B-cell ALL

Molina

Vinyoles

Granada

et al. 2020

Blood

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B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer, and high-hyperdiploidy (HyperD) identifies the most common subtype of pediatric B-ALL. Despite HyperD is an initiating oncogenic event affiliated to childhood B-ALL, the mitotic and chromosomal defects associated to HyperD B-ALL (HyperD-ALL) remain poorly characterized. Here, we have used 54 primary pediatric B-ALL samples to characterize the cellular-molecular mechanisms underlying the mitotic/chromosome defects predicated to be early pathogenic contributors in HyperD-ALL. We report that HyperD-ALL blasts are low proliferative and show a delay in early mitosis at prometaphase, associated to chromosome alignment defects at the metaphase plate leading to robust chromosome segregation defects and non-modal karyotypes. Mechanistically, biochemical, functional and mass-spectrometry assays revealed that condensin complex is impaired in HyperD-ALL cells, leading to chromosome hypocondensation, loss of centromere stiffness and mis-localization of the chromosome passenger complex proteins Aurora B Kinase (AURKB) and Survivin in early mitosis. HyperD-ALL cells show chromatid cohesion defects and impaired spindle assembly checkpoint (SAC) thus undergoing mitotic slippage due to defective AURKB and impaired SAC activity, downstream of condensin complex defects. Chromosome structure/condensation defects and hyperdiploidy were reproduced in healthy CD34+ stem/progenitor cells upon inhibition of AURKB and/or SAC. Collectively, hyperdiploid B-ALL is associated to defective condensin complex, AURKB and SAC.

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Allogeneic hematopoietic stem cell transplantation for adult patients with B-cell acute lymphoblastic leukemia with high hyperdiploidy: a retrospective nationwide study

Kurosawa

Kaito

Uchida

et al. 2021

Leukemia & Lymphoma

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High hyperdiploid acute lymphoblastic leukemia in adults shows clonal heterogeneity and chromosomal instability at diagnosis and during the course of the disease

Cited by 3 publications

References 10 publications

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

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

Impaired Condensin Complex and Aurora B kinase underlie mitotic and chromosomal defects in hyperdiploid B-cell ALL

Allogeneic hematopoietic stem cell transplantation for adult patients with B-cell acute lymphoblastic leukemia with high hyperdiploidy: a retrospective nationwide study

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