Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.
Very rare cases of human T cell acute lymphoblastic leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1, a gene encoding a transmembrane receptor that regulates normal T cell development. Here, we report that more than 50% of human T-ALLs, including tumors from all major molecular oncogenic subtypes, have activating mutations that involve the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1. These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.
Weng
Andrew P
AP
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Ferrando
Adolfo A
AA
Lee
Woojoong
W
Morris
John P
JP
Silverman
Lewis B
LB
Sanchez-Irizarry
Cheryll
C
Blacklow
Stephen C
SC
Look
A Thomas
AT
Aster
Jon C
JC
D000293:Adolescent; D000483:Alleles; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002648:Child; D019281:Dimerization; D010450:Endopeptidases / Q000378:metabolism; D016368:Frameshift Mutation; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D017354:Point Mutation; D011480:Protease Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
C497761:NOTCH1 protein, human; D011480:Protease Inhibitors; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human