Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

BRAF mutations are very rare in B- and T-cell pediatric acute lymphoblastic leukemias

Leukemia volume 22, pages 1619–1621 (2008)Cite this article

We read with interest the study by Gustafsson et al.1 regarding BRAF mutations in childhood acute lymphoblastic leukemia (ALL). They investigated exons 11 and 15 of BRAF and exons 1 and 2 of NRAS in 29 cases (25 pre-B ALL, 3 T-cell ALL and 1 undifferentiated ALL), and identified six (21%) BRAF mutations and seven (24%) NRAS mutations. The frequencies of BRAF mutations seemed to be particularly common in T-cell ALL (two out of three; 67%); only four (16%) of the pre-B ALL harbored a BRAF mutation. All mutations were located in exon 15—three L597Q and one V590I among the pre-B ALL and one V600E and one G596S in the T-cell ALL. Hou et al.2 recently demonstrated that the L597Q mutation is a functional oncogene, at least in an in vitro experimental system. In the study by Gustafsson et al.,1 and as expected based on previous studies,3, 4 the BRAF and NRAS mutations were generally mutually exclusive. The high frequency of BRAF mutations was unexpected since such mutations otherwise have been demonstrated to be very rare in hematologic malignancies. In fact, previous analyses revealed no BRAF mutations in 53 cell lines from leukemias and lymphomas,3 65 multiple myelomas/plasma cell leukemias,5 21 multiple myelomas6 or in 149 acute myeloid leukemias (AML).7, 8 We know of only three additional studies reporting acquired BRAF mutations in malignant hematologic disorders. In a series of 164 B- and T-cell lymphomas, Lee et al.9 detected BRAF mutations in ∼2.5%. The same group10 also reported such mutations in 20% of B-lineage ALL, 9% of acute biphenotypic leukemia and 4% of AML; all the investigated patients were adults. Finally, Christiansen et al.,11 who analyzed 140 treatment-related myelodysplastic syndromes and AML, found three t-AML with a BRAF mutation; all these were adult acute monoblastic leukemias with t(9;11)(p21;q23). Interestingly, germ line mutations in the closely related RAF1 (previously CRAF) were recently reported in two patients who developed t-AML.8 Hence, there may be an association between mutations in RAF genes and t-AML. It may also be noteworthy that among the 17 BRAF-positive hematologic malignancies reported to date,1, 9, 10, 11 only four (24%)—one T-cell ALL1 and three t-AML11—have carried the highly activating V600E amino-acid substitution, which results in a 500-fold activation of the BRAF protein, inducing a pronounced RAS-RAF-MEK-ERK signaling.3

To date, the report by Gustafsson et al.1 is the only one focusing on BRAF mutations in pediatric ALL, except a recent case report of a germ line BRAF mutation (E501G) in a child with a congenital cardiofaciocutaneous syndrome who later developed pre-B ALL.12 Hence, the high incidence of such mutations in childhood ALL has as yet not been confirmed. Considering that BRAF mutations may be more prevalent in some cytogenetic subgroups, as indicated by the correlation between t(9;11)-positive t-AML and BRAF mutations,11 one may expect that different karyotypic ALL entities may be associated with different mutation frequencies. Unfortunately, Gustafsson et al.1 did not include cytogenetic data. However, as most of their BRAF-positive pre-B ALL occurred in children aged 1.5–4 years, one may expect that they were characterized by either high hyperdiploidy or t(12;21)(p13;q22)/ETV6–RUNX1 fusion, as these two cytogenetic subgroups constitute approximately 80% of all B-cell precursor (BCP) ALL in the 2–7 years frequency peak,13 or by dic(9;20)(p13;q11), also known to occur primarily in this age group.14

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Gustafsson B, Angelini S, Sander B, Christensson B, Hemminki K, Kumar R . Mutations in the BRAF and N-ras genes in childhood acute lymphoblastic leukaemia. Leukemia 2005; 19: 310–312.

    Article  CAS  PubMed  Google Scholar 

  2. Hou P, Liu D, Xing M . The T1789A BRAF mutation (L597Q) in childhood acute lymphoblastic leukemia is a functional oncogene. Leukemia 2007; 21: 2216–2218.

    Article  CAS  PubMed  Google Scholar 

  3. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417: 949–954.

    Article  CAS  PubMed  Google Scholar 

  4. Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE . Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 2002; 418: 934.

    Article  CAS  PubMed  Google Scholar 

  5. Bonello L, Voena C, Ladetto M, Boccadoro M, Palestro G, Inghirami G et al. BRAF gene is not mutated in plasma cell leukemia and multiple myeloma. Leukemia 2003; 17: 2238–2240.

    Article  CAS  PubMed  Google Scholar 

  6. Ng MHL, Lau KM, Wong WS, To KW, Cheng SH, Tsang KS et al. Alterations of RAS signalling in Chinese multiple myeloma patients: absent BRAF and rare RAS mutations, but frequent inactivation of RASSF1A by transcriptional silencing or expression of a non-functional variant transcript. Br J Haematol 2003; 123: 637–645.

    Article  CAS  PubMed  Google Scholar 

  7. Smith ML, Snaddon J, Neat M, Cambal-Parrales M, Arch R, Lister TA et al. Mutation of BRAF is uncommon in AML FAB type M1 and M2. Leukemia 2003; 17: 274–275.

    Article  CAS  PubMed  Google Scholar 

  8. Zebisch A, Staber PB, Delavar A, Bodner C, Hiden K, Fischereder K et al. Two transforming C-RAF germ-line mutations identified in patients with therapy-related acute myeloid leukemia. Cancer Res 2006; 66: 3401–3408.

    Article  CAS  PubMed  Google Scholar 

  9. Lee JW, Yoo NJ, Soung YH, Kim HS, Park WS, Kim SY et al. BRAF mutations in non-Hodgkin's lymphoma. Br J Cancer 2003; 89: 1958–1960.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lee JW, Soung YH, Park WS, Kim SY, Nam SW, Min WS et al. BRAF mutations in acute leukemias. Leukemia 2004; 18: 170–172.

    Article  CAS  PubMed  Google Scholar 

  11. Christiansen DH, Andersen MK, Desta F, Pedersen-Bjergaard J . Mutations of genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 2005; 19: 2232–2240.

    Article  CAS  PubMed  Google Scholar 

  12. Makita Y, Narumi Y, Yoshida M, Niihori T, Kure S, Fujieda K et al. Leukemia in Cardio-facio-cutaneous (CFC) syndrome: a patient with a germline mutation in BRAF proto-oncogene. J Pediatr Hematol Oncol 2007; 29: 287–290.

    Article  CAS  PubMed  Google Scholar 

  13. Forestier E, Schmiegelow K . The incidence peaks of the childhood acute leukemias reflect specific cytogenetic aberrations. J Pediatr Hematol Oncol 2006; 28: 486–495.

    Article  CAS  PubMed  Google Scholar 

  14. Forestier E, Gauffin F, Andersen MK, Autio K, Borgström G, Golovleva I et al. Clinical and cytogenetic features of pediatric dic(9;20)(p13.2;q11.2)-positive B-cell precursor acute lymphoblastic leukemias: a Nordic series of 24 cases and review of the literature. Genes Chromosomes Cancer 2008; 47: 149–158.

    Article  CAS  PubMed  Google Scholar 

  15. Panagopoulos I, Mertens F, Isaksson M, Mandahl N . Absence of mutations of the BRAF gene in malignant melanoma of soft parts (clear cell sarcoma of tendons and aponeuroses). Cancer Genet Cytogenet 2005; 156: 74–76.

    Article  CAS  PubMed  Google Scholar 

  16. Paulsson K, Horvat A, Strömbeck B, Nilsson F, Heldrup J, Behrendtz M et al. Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia. Genes Chromosomes Cancer 2008; 47: 26–33.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the Swedish Children's Cancer Foundation, the Swedish Cancer Society and the Swedish Research Council.

Author information

Authors and Affiliations

  1. Department of Clinical Genetics, Lund University Hospital, Lund, Sweden

    J Davidsson, H Lilljebjörn, I Panagopoulos, T Fioretos & B Johansson

Authors
  1. J Davidsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Lilljebjörn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I Panagopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Fioretos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B Johansson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Davidsson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Davidsson, J., Lilljebjörn, H., Panagopoulos, I. et al. BRAF mutations are very rare in B- and T-cell pediatric acute lymphoblastic leukemias. Leukemia 22, 1619–1621 (2008). https://doi.org/10.1038/leu.2008.14

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.14

This article is cited by

Search

Advanced search

Quick links