Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia.
Genomic profiling has identified a subtype of high-risk B-progenitor acute lymphoblastic leukemia (B-ALL) with alteration of IKZF1, a gene expression profile similar to BCR-ABL1-positive ALL and poor outcome (Ph-like ALL). The genetic alterations that activate kinase signaling in Ph-like ALL are poorly understood. We performed transcriptome and whole genome sequencing on 15 cases of Ph-like ALL and identified rearrangements involving ABL1, JAK2, PDGFRB, CRLF2, and EPOR, activating mutations of IL7R and FLT3, and deletion of SH2B3, which encodes the JAK2-negative regulator LNK. Importantly, several of these alterations induce transformation that is attenuated with tyrosine kinase inhibitors, suggesting the treatment outcome of these patients may be improved with targeted therapy.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Kathryn G
KG
Roberts
Ryan D
RD
Morin
Jinghui
J
Zhang
Martin
M
Hirst
Yongjun
Y
Zhao
Xiaoping
X
Su
Shann-Ching
SC
Chen
Debbie
D
Payne-Turner
Michelle L
ML
Churchman
Richard C
RC
Harvey
Xiang
X
Chen
Corynn
C
Kasap
Chunhua
C
Yan
Jared
J
Becksfort
Richard P
RP
Finney
David T
DT
Teachey
Shannon L
SL
Maude
Kane
K
Tse
Richard
R
Moore
Steven
S
Jones
Karen
K
Mungall
Inanc
I
Birol
Michael N
MN
Edmonson
Ying
Y
Hu
Kenneth E
KE
Buetow
I-Ming
IM
Chen
William L
WL
Carroll
Lei
L
Wei
Jing
J
Ma
Maria
M
Kleppe
Ross L
RL
Levine
Guillermo
G
Garcia-Manero
Eric
E
Larsen
Neil P
NP
Shah
Meenakshi
M
Devidas
Gregory
G
Reaman
Malcolm
M
Smith
Steven W
SW
Paugh
William E
WE
Evans
Stephan A
SA
Grupp
Sima
S
Jeha
Ching-Hon
CH
Pui
Daniela S
DS
Gerhard
James R
JR
Downing
Cheryl L
CL
Willman
Mignon
M
Loh
Stephen P
SP
Hunger
Marco A
MA
Marra
Charles G
CG
Mullighan
D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic; D004252:DNA Mutational Analysis; D004789:Enzyme Activation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D015321:Gene Rearrangement / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010677:Philadelphia Chromosome; D010766:Phosphorylation / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology* / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics; D018121:Receptors, Cytokine / Q000235:genetics*; D012008:Recurrence; D012307:Risk Factors; D017384:Sequence Deletion / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics
C081976:EBF1 protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta