BRAF mutations in acute leukemias

Lee, Jung Woo; Soung, Young Hwa; Park, W S; Kim, S Y; Nam, Suk Woo; Min, Woo Sung; Yoo, Nam Jin; Lee, S H

doi:10.1038/sj.leu.2403201

Cited by 42 publications

(26 citation statements)

References 8 publications

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“…Due to more innovative, high-throughput DNA sequencing, scientists have recently discovered that the B-Raf gene is frequently mutated in certain cancers, including hematopoietic tumors such as nonHodgkin's lymphoma and acute myelogenous leukemia (38,39). Approximately 60% of the melanomas surveyed in one study were observed to have mutations at B-Raf (40).…”

Section: Discussionmentioning

confidence: 99%

Development of a Conditional In vivo Model to Evaluate the Efficacy of Small Molecule Inhibitors for the Treatment of Raf-Transformed Hematopoietic Cells

Konopleva¹,

Shi²,

Steelman³

et al. 2005

Cancer Research

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Conditionally active forms of the Raf proteins (Raf-1, B-Raf, and A-Raf) were created by ligating NH 2 -terminal truncated activated forms (#) to the estrogen receptor (ER) hormonebinding domain resulting in estradiol-regulated constructs (#Raf:ER). These different Raf:ER oncoproteins were introduced into the murine FDC-P1 hematopoietic cell line, and cells that grew in response to the three #Raf:ER oncoproteins were isolated. The ability of FDC-P1, #Raf-1:ER, #A-Raf:ER, and #B-Raf:ER cells to form tumors in severe combined immunodeficient mice was compared. Mice injected with #Raf:ER cells were implanted with B-estradiol pellets to induce the #Raf:ER oncoprotein. Cytokine-dependent parental cell lines did not form tumors. Implantation of B-estradiol pellets into mice injected with #Raf:ER cells significantly accelerated tumor onset and tumor size. The recovered #Raf:ER cells displayed induction of extracellular signalregulated kinase (ERK) in response to B-estradiol stimulation, indicating that they had retained conditional activation of ERK even when passed through a severe combined immunodeficient mouse. The #Raf:ER cells were very sensitive to induction of apoptosis by the mitogen-activated protein/ERK kinase (MEK) 1 inhibitor CI1040 whereas parental cells were much less affected, demonstrating that the MEK1 may be useful in eliminating Ras/Raf/MEK-transformed cells. Furthermore, the effects of in vivo administration of the MEK1 inhibitor were evaluated and this inhibitor was observed to suppress the tumorigenicity of the injected cells. This #Raf:ER system can serve as a preclinical model to evaluate the effects of signal transduction inhibitors which target the Raf and MEK proteins. (Cancer Res 2005; 65(21): 9962-70)

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Section: Discussionmentioning

confidence: 99%

Development of a Conditional In vivo Model to Evaluate the Efficacy of Small Molecule Inhibitors for the Treatment of Raf-Transformed Hematopoietic Cells

Konopleva¹,

Shi²,

Steelman³

et al. 2005

Cancer Research

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“…Mutations in RAF and SOS1, which are also part of the RAS pathway, are rarely found in AML. [89][90][91] Mutations in FLT3 and KIT are rare in MLL-rearranged AML. 88,92 Recently, novel molecular aberrations were found in pediatric AML, that is, mutations in NPM1, CEBPA and WT1.…”

Section: Molecular Abnormalities In Mll-rearranged Amlmentioning

confidence: 99%

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

et al. 2011

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Translocations involving the mixed-lineage leukemia (MLL) gene, localized at 11q23, comprise 15 to 20% of all pediatric acute myeloid leukemia (AML) cases. This review summarizes current knowledge about the etiology, biology, clinical characteristics and differences in outcome in MLL-rearranged pediatric AML. Furthermore, we discuss the role of cooperating events in MLL-rearranged pediatric AML, and future therapeutic strategies to improve outcome. We conclude that MLL-rearranged pediatric AML is a heterogeneous disease, and prognosis depends on various factors, for example, translocation partner, age, WBC and additional cytogenetic aberrations. The relationship of outcome with specific translocation partners requires that they be searched for in the diagnostic work-up of AML. To achieve further improvements in outcome, unraveling the biology of MLL-rearranged pediatric AML is warranted.

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“…5,6 In a recent report on acute leukaemia, a low frequency of mutations was reported in the G-loop within the kinase domain of BRAF. 7 Considering the importance of the Ras/Raf/MAP-kinase pathways in leukaemia, we examined bone marrows from 29 cases of childhood ALL for mutations in the N-ras and BRAF genes.…”

Section: Figurementioning

confidence: 99%