High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients

Jeffrey Tyner, Heidi Erickson, Michael W N Deininger, Stephanie G. Willis, Christopher A. Eide, Ross L. Levine, Michael Heinrich, Norbert Gattermann, D. Gary Gilliland, Brian Druker, Marc Loriaux

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

Transforming mutations in NRAS and KRAS are thought to play a causative role in the development of numerous cancers, including myeloid malignancies. Although mutations at amino acids 12, 13, or 61 account for the majority of oncogenic Ras variants, we hypothesized that less frequent mutations at alternate residues may account for disease in some patients with cancer of unexplained genetic etiology. To search for additional, novel RAS mutations, we sequenced all coding exons in NRAS, KRAS, and HRAS in 329 acute myeloid leukemia (AML) patients, 32 chronic myelomonocytic leukemia (CMML) patients, and 96 healthy individuals. We detected 4 "noncanonical" point mutations in 7 patients: N-Ras G60E, K-Ras V14I, K-Ras T74P, and K-Ras A146T. All 4 Ras mutants exhibited oncogenic properties incomparison with wild-type Ras in biochemical and functional assays. The presence of transforming RAS mutations outside of positions 12, 13, and 61 reveals that alternate mechanisms of transformation by RAS may be overlooked in screens designed to detect only the most common RAS mutations. Our results suggest that RAS mutations may play a greater role in leukemogenesis than currently believed and indicate that high-throughput screening for mutant RAS alleles in cancer should include analysis of the entire RAS coding region.

Original languageEnglish (US)
Pages (from-to)1749-1755
Number of pages7
JournalBlood
Volume113
Issue number8
DOIs
StatePublished - Feb 19 2009

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Myeloid Leukemia
Exons
Assays
Screening
Throughput
Amino Acids
Mutation
Neoplasms
Leukemia, Myelomonocytic, Chronic
Point Mutation
Acute Myeloid Leukemia
Alleles

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients. / Tyner, Jeffrey; Erickson, Heidi; Deininger, Michael W N; Willis, Stephanie G.; Eide, Christopher A.; Levine, Ross L.; Heinrich, Michael; Gattermann, Norbert; Gilliland, D. Gary; Druker, Brian; Loriaux, Marc.

In: Blood, Vol. 113, No. 8, 19.02.2009, p. 1749-1755.

Research output: Contribution to journalArticle

Tyner, J, Erickson, H, Deininger, MWN, Willis, SG, Eide, CA, Levine, RL, Heinrich, M, Gattermann, N, Gilliland, DG, Druker, B & Loriaux, M 2009, 'High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients', Blood, vol. 113, no. 8, pp. 1749-1755. https://doi.org/10.1182/blood-2008-04-152157
Tyner, Jeffrey ; Erickson, Heidi ; Deininger, Michael W N ; Willis, Stephanie G. ; Eide, Christopher A. ; Levine, Ross L. ; Heinrich, Michael ; Gattermann, Norbert ; Gilliland, D. Gary ; Druker, Brian ; Loriaux, Marc. / High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients. In: Blood. 2009 ; Vol. 113, No. 8. pp. 1749-1755.
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