title: Prognostic and therapeutic role of targetable lesions in B-lineage acute lymphoblastic leukemia without recurrent fusion genes.
abstract: To shed light into the molecular bases of B-lineage acute lymphoblastic leukemia lacking known fusion transcripts, i.e. BCR-ABL1, ETV6-RUNX1, E2A-PBX1, and MLL rearrangements (B-NEG ALL) and the differences between children, adolescents/young adults (AYA) and adults, we analyzed 168 B-NEG ALLs by genome-wide technologies. This approach showed that B-NEG cases carry 10.5 mutations and 9.1 copy-number aberrations/sample. The most frequently mutated druggable pathways were those pertaining to RAS/RTK (26.8%) and JAK/STAT (12.5%) signaling. In particular, FLT3 and JAK/STAT mutations were detected mainly in AYA and adults, while KRAS and NRAS mutations were more frequent in children. RAS/RTK mutations negatively affected the outcome of AYA and adults, but not that of children. Furthermore, adult B-NEG ALL carrying JAK/STAT mutations had a shorter survival. In vitro experiments showed that FLT3 inhibitors reduced significantly the proliferation of FLT3-mutated primary B-NEG ALL cells. Likewise, PI3K/mTOR inhibitors reduced the proliferation of primary cells harboring RAS and IL7R mutations. These results refine the genetic landscape of B-NEG ALL and suggest that the different distribution of lesions and their prognostic impact might sustain the diverse outcome between children, adults and partly AYA - whose genomic scenario is similar to adults - and open the way to targeted therapeutic strategies.
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Messina
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Chiaretti
authors.affiliation: Department of Systems Biology, Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA.
authors.forename: Jiguang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Anna Lucia
authors.initials: AL
authors.lastname: Fedullo
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Peragine
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Gianfelici
authors.affiliation: GIMEMA Data Center, Rome, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Piciocchi
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Fulvia
authors.initials: F
authors.lastname: Brugnoletti
authors.affiliation: Department of Molecular Biotechnology and Health Science, and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.
authors.forename: Filomena
authors.initials: F
authors.lastname: Di Giacomo
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Pauselli
authors.affiliation: Institute for Cancer Genetics and The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
authors.forename: Antony B
authors.initials: AB
authors.lastname: Holmes
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Puzzolo
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ceglie
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Apicella
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Mancini
authors.affiliation: Department of Women's and Children's Health, University of Padova, Padova, Italy.
authors.forename: Geertruy
authors.initials: G
authors.lastname: Te Kronnie
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Testi
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Vitale
authors.affiliation: GIMEMA Data Center, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Vignetti
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Guarini
authors.affiliation: Department of Systems Biology, Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D019070:Cell Lineage; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000401:mortality* / Q000628:therapy; D011379:Prognosis; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D015514:Oncogene Proteins, Fusion
keywords: acute lymphoblastic leukemia; copy number aberrations; genetic-driven targeted therapy; next generation sequencing; novel prognostic markers