Novel oncogenic mutations of CBL in human acute myeloid leukemia that activate growth and survival pathways depend on increased metabolism.

The Journal of Biological Chemistry
Margret S FernandesMartin Sattler

Abstract

Acute myeloid leukemia (AML) is characterized by multiple mutagenic events that affect proliferation, survival, as well as differentiation. Recently, gain-of-function mutations in the α helical structure within the linker sequence of the E3 ubiquitin ligase CBL have been associated with AML. We identified four novel CBL mutations, including a point mutation (Y371H) and a putative splice site mutation in AML specimens. Characterization of these two CBL mutants revealed that coexpression with the receptor tyrosine kinases FLT3 (Fms-like tyrosine kinase 3) or KIT-induced ligand independent growth or ligand hyperresponsiveness, respectively. Growth of cells expressing mutant CBL required expression and kinase activity of FLT3. In addition to the CBL-dependent phosphorylation of FLT3 and CBL itself, transformation was associated with activation of Akt and STAT5 and required functional expression of the small GTPases Rho, Rac, and Cdc42. Furthermore, the mutations led to constitutively elevated intracellular reactive oxygen species levels, which is commonly linked to increased glucose metabolism in cancer cells. Inhibition of hexokinase with 2-deoxyglucose blocked the transforming activity of CBL mutants and reduced activation of sig...Continue Reading

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Citations

Dec 14, 2011·Proceedings of the National Academy of Sciences of the United States of America·Yoshihiro KobashigawaFuyuhiko Inagaki
Sep 10, 2011·Therapeutic Advances in Medical Oncology·Martin SattlerRavi Salgia
Jul 18, 2012·Leukemia & Lymphoma·Paula AranazJosé Luis Vizmanos
Feb 22, 2012·Trends in Immunology·Kelly Moran-CrusioIannis Aifantis
Oct 3, 2012·British Journal of Haematology·Eva A CoenenMarry M van den Heuvel-Eibrink
May 13, 2015·Molecular Therapy. Nucleic Acids·Breanne LandryHasan Uludag
Jan 10, 2019·International Journal of Molecular Sciences·Qi-Yuan HuangLi-Xia Xiong
May 4, 2018·Nature Communications·Axel Hyrenius-WittstenAnna K Hagström-Andersson
Feb 6, 2020·British Journal of Cancer·Jing YangJames D Griffin
Jan 14, 2017·The Journal of Biological Chemistry·Scott A NadeauHamid Band
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Jan 17, 2020·Journal of Cellular and Molecular Medicine·Ellen WeisbergJames D Griffin
Sep 10, 2021·Current Hematologic Malignancy Reports·Danielle Hammond, Guillermo Montalban-Bravo

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