Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness

Monica Messina, Ilaria Del Giudice, Hossein Khiabanian, Davide Rossi, Sabina Chiaretti, Silvia Rasi, Valeria Spina, Antony B. Holmes, Marilisa Marinelli, Giulia Fabbri, Alfonso Piciocchi, Francesca R. Mauro, Anna Guarini, Gianluca Gaidano, Riccardo Dalla-Favera, Laura Pasqualucci, Raul Rabadan, Robin Foà

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

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 5 .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.

Original languageEnglish (US)
Pages (from-to)2378-2388
Number of pages11
JournalBlood
Volume123
Issue number15
DOIs
StatePublished - Apr 10 2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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