Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia

Caligiuri, Michael A.; Briesewitz, Roger; Yu, Jianhua; Wang, Lisheng; Min, Wei; Arnoczky, Kristy J.; Marburger, Trent B.; Wen, Jing; Perrotti, Danilo; Bloomfield, Clara D.; Whitman, Susan P.

doi:10.1182/blood-2006-12-061176

Cited by 142 publications

(140 citation statements)

References 23 publications

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“…Recent reports have shown that mutations in the Cbl family RING finger domain are not only associated with preleukemic chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, and other myeloproliferative neoplasms, but also with progression to AML (31,32). It is well known that the inhibition of PI3K/Akt activation by Cbl-b is dependent on a functional Cbl RING finger (18)(19)(20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

Li¹,

Qu²,

Qu³

et al. 2011

Braz J Med Biol Res

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Arsenic trioxide (ATO) is a strong inducer of apoptosis in malignant hematological cells. Inducible phosphatidyl inositol 3 kinase (PI3K)-Akt activation promotes resistance to ATO. In the present study, we evaluated whether E3 ubiquitin ligase Cbl-b, a negative regulator of PI3K activation, is involved in the action of ATO. The effect of ATO on cell viability was measured by the Trypan blue exclusion assay or by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was determined by flow cytometry and protein expression was assayed by Western blotting. ATO decreased the viability of HL60 cells and induced cellular apoptosis, which was accompanied by transient activation of Akt. The PI3K/Akt inhibitor, LY294002, significantly increased ATO-induced apoptosis (P < 0.05). In addition, ATO up-regulated the expression of Cbl-b proteins. Furthermore, ATO inhibited cell viability with an IC 50 of 18.54 μM at 24 h in rat basophilic leukemia-2H3 cells. ATO induced cellular apoptosis with transient activation of Akt and Cbl-b was also up-regulated. Rat basophilic leukemia-2H3 cells transfected with a dominant negative (DN) Cbl-b mutation showed overexpression of Cbl-b (DN) and enhanced Akt activation. Compared with cells transfected with vector, ATO-induced apoptosis was decreased and G2/M phase cells were increased at the same concentration (P < 0.05). The PI3K/Akt inhibitor, LY294002, re-sensitized Cbl-b (DN) overexpressing cells to ATO and reversed G2/M arrest (P < 0.05). Taken together, these results suggest that Cbl-b potentiates the apoptotic action of ATO by inhibition of the PI3K/Akt pathway.

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Section: Discussionmentioning

confidence: 99%

E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

Li¹,

Qu²,

Qu³

et al. 2011

Braz J Med Biol Res

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“…CBL mutations have been found in various myeloid malignancies, such as MDS, AML, and chronic myelomonocytic leukemia (CMML) [33][34][35]. CBL mutations have also been identified in the patients with FPD/AML.…”

Section: Additional Genetic Events For Mutant Clone Expansion and Leumentioning

confidence: 99%

Myeloid neoplasms with germ line RUNX1 mutation

et al. 2017

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“…The prevalence and clinical significance of these mutations in AML remains to be determined. 102,103 Mutations that impair myeloid differentiation…”

Section: Ptpn11mentioning

confidence: 99%

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

et al. 2008

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Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders with great variability in clinical course and response to therapy, as well as in the genetic and molecular basis of the pathology. Major advances in the understanding of leukemogenesis have been made by the characterization and the study of acquired cytogenetic abnormalities, particularly reciprocal translocations observed in AML. Besides these major cytogenetic abnormalities, gene mutations also constitute key events in AML pathogenesis. In this review, we describe the contribution of known gene mutations to the understanding of AML pathogenesis and their clinical significance. To gain more insight in this understanding, we clustered these alterations in three groups: (1) mutations affecting genes that contribute to cell proliferation (FLT3, c-KIT, RAS, protein tyrosine standard phosphatase nonreceptor 11); (2) mutations affecting genes involved in myeloid differentiation (AML1 and CEBPA) and (3) mutations affecting genes implicated in cell cycle regulation or apoptosis (P53, NPM1). This nonexhaustive review aims to show how gene mutations interact with each other, how they contribute to refine prognosis and how they can be useful for risk-adapted therapeutic management of AML patients.

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Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia

Cited by 142 publications

References 23 publications

E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

Myeloid neoplasms with germ line RUNX1 mutation

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

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