Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia.
Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. We report that somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis. All mutations were missense, and some were predicted to destabilize interdomain interactions controlling the activity of the kinase. Three mutations that were studied promoted JAK1 gain of function and conferred interleukin (IL)-3-independent growth in Ba/F3 cells and/or IL-9-independent resistance to dexamethasone-induced apoptosis in T cell lymphoma BW5147 cells. Such effects were associated with variably enhanced activation of multiple downstream signaling pathways. Leukemic cells with mutated JAK1 alleles shared a gene expression signature characterized by transcriptional up-regulation of genes positively controlled by JAK signaling. Our findings implicate dysregulated JAK1 function in ALL, particularly of T cell origin, and point to this kinase as a target for the development of novel antileukemic drugs.
Flex
Elisabetta
E
Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome, 00161, Italy.
Petrangeli
Valentina
V
Stella
Lorenzo
L
Chiaretti
Sabina
S
Hornakova
Tekla
T
Knoops
Laurent
L
Ariola
Cristina
C
Fodale
Valentina
V
Clappier
Emmanuelle
E
Paoloni
Francesca
F
Martinelli
Simone
S
Fragale
Alessandra
A
Sanchez
Massimo
M
Tavolaro
Simona
S
Messina
Monica
M
Cazzaniga
Giovanni
G
Camera
Andrea
A
Pizzolo
Giovanni
G
Tornesello
Assunta
A
Vignetti
Marco
M
Battistini
Angela
A
Cavé
Hélène
H
Gelb
Bruce D
BD
Renauld
Jean-Christophe
JC
Biondi
Andrea
A
Constantinescu
Stefan N
SN
Foà
Robin
R
Tartaglia
Marco
M
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology
D050505:Mutant Proteins; D053613:Janus Kinase 1