Menéndez, P. (Pablo)

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    Clonal heterogeneity and rates of specific chromosome gains are risk predictors in childhood high-hyperdiploid B-cell acute lymphoblastic leukemia
    (2022) Velasco, P. (Pablo); Ballerini, P. (Paola); Boer, J. (Judith); Schwab, C. (Claire); Camós, Mencia; Bataller, A. (Álex); López-Millán, B. (Belén); Cuatrecasas, E. (Esther); Rodríguez-Cortez, V.C. (Virginia C.); Blanco, M.L. (María Laura); Cazzaniga, G.; Ramos-Muntada, M. (Mireia); Bueno, C. (Clara); Fuster, (J.L.) Jose L.; Blanco, J. (Joan); DenBoer, M. (Monique); Ramírez-Orellana, M. (Manuel ); Harrison, C.J. (Christine J.); Hernandez-Rivas, J.M. (Jesús M.); Minguela, (A.) Alfredo; Nomdedeu, J. (Josep); Escherich, G. (Gabriele); Calasanz-Abinzano, M.J. (Maria Jose); Menéndez, P. (Pablo); Trincado, J.L. (Juan L.); Ortega, M. (Margarita); Molina, O. (Oscar)
    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.