Implicación de las alteraciones en el número de copias en el pronóstico y progresión de la leucemia aguda linfoblástica de línea B del adulto

Abstract

Approximately, 75% of acute lymphoblastic leukemia (ALL) patients show recurrent chromosomal abnormalities (numerical and structural). These are primary alterations that have been extensively related to patients’ prognosis. The predictive value of these chromosomal aberrations is taken into account for treatment assignment. However, the prognostic value of secondary alterations (i.e., point mutations or copy number alterations) is less clear. These alterations may play an important role in the response to the therapy, as not all patients with the same karyotype show the same response to treatment. With the aim to identify new prognostic markers in patients with B lineage ALL, the frequency and prognostic significance of copy number alterations (CNA) in patients with mature and precursor B ALL have been analyzed. In the first study of this Doctoral Thesis EBF1, IKZF1 and CDKN2A/B deletions at diagnosis were identified as markers with independent prognostic value in a series of 142 adolescent and adult patients with precursor B ALL. Specifically, EBF1 deletions were associated with a lower probability of achieving complete remission, IKZF1 deletions were related to a greater relapse probability while CDKN2A/B deletions were present in patients with lower survival probability. Therefore, the detection of these genetic alterations identifies a subset of high risk patients who may benefit from a more intensive treatment, while new and more specific treatments are developed against these alterations. In the second study, a clear difference in the genetic profiles of mature B and precursor B ALL was observed. In this sense, the frequency of the alterations associated with poor prognosis detected in the first study was much lower in mature B ALL compared to precursor B ALL patients. This fact may explain, in part, the better prognosis of mature B compared to that of precursor B ALL. However, although some deletions potentially related to the aggressiveness and dissemination of mature B ALL (CDKN2A / B, RB1 and 14q32.33 region) were detected, no CNAs with prognostic value could be identified in these patients. Finally, relapse samples of patients with precursor B ALL were analyzed in the third study. Comparison of paired diagnostic and relapse samples from each patient showed a significant increase in the number of CNAs during the progression of leukemia. In addition, a great diversity of metabolic pathways affected by CNA without a recurrent genetic signature at relapse was evidenced, except for the acquisition of homozygous deletions in the CDKN2A/B gene (~50% frequency). The most frequently involved metabolic pathways at relapse were those related with differentiation of B lymphocytes, cell cycle control and apoptosis, among others. Alterations in genes involved in cell proliferation, hematopoietic stem cell homeostasis, and drug resistance were the most common among the newly acquired CNAs at relapse. With the exception of one patient, all patients showed at relapse genetic changes compared to the diagnosis and most relapses came from an ancestral clone to that detected at the time of diagnosis. The identification of relapse-specific CNAs may contribute to the design of new treatments that could increase the probability of survival of relapsed patients, which currently stands at 10%.

Date of Award	20 Sept 2017
Original language	Spanish
Supervisor	Lurdes Zamora Plana (Director) & Jose Maria Ribera Santasusana (Director)