Common nonmutationalNOTCH1activation in chronic lymphocytic leukemia.
Activating mutations ofNOTCH1(a well-known oncogene in T-cell acute lymphoblastic leukemia) are present in ∼4-13% of chronic lymphocytic leukemia (CLL) cases, where they are associated with disease progression and chemorefractoriness. However, the specific role ofNOTCH1in leukemogenesis remains to be established. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ∼50% of peripheral blood CLL cases lacking gene mutations. We identify a "NOTCH1 gene-expression signature" in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent ofNOTCH1mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival, and signal transduction. In particular, we show that NOTCH1 transactivatesMYCvia binding to B-cell-specific regulatory elements, thus implicating this oncogene in CLL development. These results significantly extend the role ofNOTCH1in CLL pathogenesis, and have direct implications for specific therapeutic targeting.
Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
Giulia
G
Fabbri
Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
Antony B
AB
Holmes
Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
Mara
M
Viganotti
Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
Claudio
C
Scuoppo
Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
Laura
L
Belver
Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
Daniel
D
Herranz
The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, NY 11030.
Xiao-Jie
XJ
Yan
The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, NY 11030.
Yasmine
Y
Kieso
Division of Hematology, Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland.|Lymphoma and Genomics Research Program, Institute of Oncology Research, 6500 Bellinzona, Switzerland.
Davide
D
Rossi
Division of Haematology, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy.
Gianluca
G
Gaidano
The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, NY 11030.
Nicholas
N
Chiorazzi
Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.|Department of Pathology and Cell Biology, Columbia University, New York, NY 10032.|Department of Pediatrics, Columbia University, New York, NY 10032.
Adolfo A
AA
Ferrando
Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032; rd10@columbia.edu.|Department of Pathology and Cell Biology, Columbia University, New York, NY 10032.|Department of Genetics & Development, Columbia University, New York, NY 10032.|Department of Microbiology & Immunology, Columbia University, New York, NY 10032.
Riccardo
R
Dalla-Favera
D001402:B-Lymphocytes / Q000473:pathology / Q000502:physiology*; D049109:Cell Proliferation / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D016259:Genes, myc; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D009154:Mutation; D051881:Receptor, Notch1 / Q000097:blood / Q000235:genetics*
C497761:NOTCH1 protein, human; D051881:Receptor, Notch1
NOTCH1; chronic lymphocytic leukemia; transcriptional network