Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia.
The CBL ubiquitin ligase targets a variety of activated tyrosine kinases (TKs) for degradation. Many TKs are mutationally or autocrine activated and/or often overexpressed at the mRNA and protein levels in acute leukemias. We hypothesized that CBL is mutated in patients with acute myeloid leukemia (AML). Four of 12 patients and the MOLM-13 cell line harbored c-CBL mutations, either RNA splicing mutations, missense mutations, or a nucleotide insertion. Additionally, 1 of the 12 patients harbored a missense mutation in the related CBL-b gene. Each c-CBL mutation involves the structurally important alpha-helix within the linker region, while the mutation in CBL-b was located in the Ub-E2 protein-binding RING finger. Short-interfering RNA knockdown of mutant c-CBL present in MOLM-13 cells was growth inhibitory. In summary, novel mutations in c-CBL and CBL-b have been identified in human AML and may represent potential targets for novel therapeutics.
Caligiuri
Michael A
MA
Integrated Biomeducal Graduate Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH 23240, USA.
Briesewitz
Roger
R
Yu
Jianhua
J
Wang
Lisheng
L
Wei
Min
M
Arnoczky
Kristy J
KJ
Marburger
Trent B
TB
Wen
Jing
J
Perrotti
Danilo
D
Bloomfield
Clara D
CD
Whitman
Susan P
SP
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D020125:Mutation, Missense; D017433:Protein Structure, Secondary / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D034741:RNA, Small Interfering; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D011505:Protein-Tyrosine Kinases; C067419:CBL protein, human