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The T1790A BRAF mutation (L597Q) in childhood acute lymphoblastic leukemia is a functional oncogene

Leukemia volume 21, pages 2216–2218 (2007)Cite this article

Since the initial report of the BRAF mutation in human cancers,1 over 40 missense mutations have been identified in this gene, among which the T1799A point mutation in exon 15 accounts for up to 90%.2 This mutation causes a V600E amino-acid substitution in codon 600 and converts BRAF into a constitutively activated dominant transforming protein kinase, BRAFV600E, which causes cancer through aberrant activation of the Ras/Raf/MEK/MAP kinase/ERK signaling pathway (MAP kinase pathway).1, 2, 3 Several other uncommon mutations of the BRAF gene are also well characterized and may play an important role in the tumorigenesis of certain human cancers.1, 2, 3, 4, 5, 6 A recent study reported an interesting T1790A point mutation in exon 15 of the BRAF gene in 10% of patients with childhood acute lymphoblastic leukemia (ALL).7 This mutation is in codon 597, three codons upstream of codon 600 that carries the conventional T1799A mutation in the BRAF gene. The codon change (CTA to CAA) resulting from this new mutation causes a leucine-to-glutamine amino-acid change (L597Q) in the BRAF protein. Whether this fairly common BRAFL597Q in childhood ALL is functional and oncogenic remains to be determined.

To investigate further the oncogenic function of BRAFL597Q, we examined its transforming ability by comparing colony formation of various BRAF transfectants of NIH3T3 cells on soft agar. We found significant colony formation with the two activating mutants, BRAFV600E and BRAFL597Q, in a similar manner (Figures 1b and c). No colony formation occurred with vector transfections (control). We also did not see colony formation with the BRAFWT transfectant. This was an expected result as the BRAFWT itself is not oncogenic and BRAFWT was unable to overactivate the MAP kinase pathway (Figure 1a). These data demonstrated the transforming ability of the T1790A BRAF mutation and, together with its constitutive kinase activation of BRAF (Figure 1a), demonstrated its oncogenic function.

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Acknowledgements

We thank Dr Richard Marais for providing us the plasmid constructs encoding BRAFWT and BRAFV600E. This study is supported by an American Cancer Society grant (RSG-05-199-01-CCE) to MX.

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  1. P Hou and D Liu: These two authors contributed equally to this work.

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  1. Division of Endocrinology and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    P Hou, D Liu & M Xing

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Correspondence to M Xing.

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Hou, P., Liu, D. & Xing, M. The T1790A BRAF mutation (L597Q) in childhood acute lymphoblastic leukemia is a functional oncogene. Leukemia 21, 2216–2218 (2007). https://doi.org/10.1038/sj.leu.2404761

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