title: Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness.
abstract: Fludarabine refractoriness (FR) represents an unsolved clinical problem of chronic lymphocytic leukemia (CLL) management. Although next-generation sequencing studies have led to the identification of a number of genes frequently mutated in FR-CLL, a comprehensive evaluation of the FR-CLL genome has not been reported. Toward this end, we studied 10 FR-CLLs by combining whole-exome sequencing and copy number aberration (CNA) analysis, which showed an average of 16.3 somatic mutations and 4 CNAs per sample. Screening of recurrently mutated genes in 48 additional FR-CLLs revealed that ~70% of FR-CLLs carry ≥1 mutation in genes previously associated with CLL clinical course, including TP53 (27.5%), NOTCH1 (24.1%), SF3B1 (18.9%), and BIRC3 (15.5%). In addition, this analysis showed that 10.3% of FR-CLL cases display mutations of the FAT1 gene, which encodes for a cadherin-like protein that negatively regulates Wnt signaling, consistent with a tumor suppressor role. The frequency of FAT1-mutated cases was significantly higher in FR-CLL than in unselected CLLs at diagnosis (10.3% vs 1.1%, P = .004), suggesting a role in the development of a high-risk phenotype. These findings have general implications for the mechanisms leading to FR and point to Wnt signaling as a potential therapeutic target in FR-CLL.
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy;
authors.forename: Monica
authors.initials: M
authors.lastname: Messina
authors.forename: Ilaria
authors.initials: I
authors.lastname: Del Giudice
authors.forename: Hossein
authors.initials: H
authors.lastname: Khiabanian
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Sabina
authors.initials: S
authors.lastname: Chiaretti
authors.forename: Silvia
authors.initials: S
authors.lastname: Rasi
authors.forename: Valeria
authors.initials: V
authors.lastname: Spina
authors.forename: Antony B
authors.initials: AB
authors.lastname: Holmes
authors.forename: Marilisa
authors.initials: M
authors.lastname: Marinelli
authors.forename: Giulia
authors.initials: G
authors.lastname: Fabbri
authors.forename: Alfonso
authors.initials: A
authors.lastname: Piciocchi
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Mauro
authors.forename: Anna
authors.initials: A
authors.lastname: Guarini
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
mesh_terms: D000368:Aged; D015820:Cadherins / Q000235:genetics*; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059467:Transcriptome
chemical_list: D015820:Cadherins; C502403:FAT1 protein, human