title: NOTCH1 mutations in CLL associated with trisomy 12.
abstract: Two recent studies reported whole-genome sequencing of chronic lymphocytic leukemia (CLL) samples and found repeated mutations in the XPO1 and NOTCH1 genes. XPO1 was found mutated in 2.4% of cases, while NOTCH1 was found mutated in 12.2% or 15.1% of CLL samples. Here we report the results of sequencing of XPO1 and NOTCH1 in 186 CLL cases. Our results confirmed frequency of XPO1 mutations. However, we found only 5 NOTCH1 mutations in 127 IGVH unmutated/ZAP70(+) CLL samples (4%), and one mutation was found in IGVH mutated/ZAP70(-) CLL for a total percentage of 1.5%. Because 4 of 6 mutated samples also showed trisomy 12, we sequenced NOTCH1 in an additional 77 cases with trisomy 12 CLLs, including 47 IGVH unmutated/ZAP70(+) cases. Importantly, we found 41.9% NOTCH1 mutation frequency in aggressive trisomy 12 CLL cases. Our data suggest that activation of NOTCH1 plays a critical role in IGVH unmutated/ZAP70(+) trisomy 12 CLL.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Balatti
authors.forename: Arianna
authors.initials: A
authors.lastname: Bottoni
authors.forename: Alexey
authors.initials: A
authors.lastname: Palamarchuk
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Laura Z
authors.initials: LZ
authors.lastname: Rassenti
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: Yuri
authors.initials: Y
authors.lastname: Pekarsky
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D015331:Cohort Studies; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D011379:Prognosis; D051881:Receptor, Notch1 / Q000235:genetics*; D014314:Trisomy; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human
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