Characterization of the leukemogenic potential of distal cytoplasmic CSF3R truncation and missense mutations

H. Zhang, A. Reister Schultz, S. Luty, A. Rofelty, Y. Su, S. Means, D. Bottomly, Beth Wilmot, Shannon McWeeney, Jeffrey Tyner

Research output: Contribution to journalArticle

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Abstract

An increasing number of variants of unknown significance are being identified in leukemia patients with the application of deep sequencing and these include CSF3R cytoplasmic mutations. Previous studies have demonstrated oncogenic potential of certain CSF3R truncation mutations prior to internalization motifs. However, the oncogenic potential of truncating the more distal region of CSF3R cytoplasmic domain as well as cytoplasmic missense mutations remains uncharacterized. Here we identified that CSF3R distal cytoplasmic truncation mutations (Q793-Q823) also harbored leukemogenic potential. Mechanistically, these distal cytoplasmic truncation mutations demonstrated markedly decreased receptor degradation, probably owing to loss of the de-phosphorylation domain (residues N818-F836). Furthermore, all truncations prior to Q823 demonstrated increased expression of the higher molecular weight CSF3R band, which is shown to be essential for the receptor surface expression and the oncogenic potential. We further demonstrated that sufficient STAT5 activation is essential for oncogenic potential. In addition, CSF3R K704A demonstrated transforming capacity due to interruption of receptor ubiquitination and degradation. In summary, we have expanded the region of the CSF3R cytoplasmic domain in which truncation or missense mutations exhibit leukemogenic capacity, which will be useful for evaluating the relevance of CSF3R mutations in patients and helpful in defining targeted therapy strategies.

Original languageEnglish (US)
Pages (from-to)2752-2760
Number of pages9
JournalLeukemia
Volume31
Issue number12
DOIs
StatePublished - Dec 1 2017

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Missense Mutation
Mutation
High-Throughput Nucleotide Sequencing
Ubiquitination
Leukemia
Molecular Weight
Phosphorylation

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Characterization of the leukemogenic potential of distal cytoplasmic CSF3R truncation and missense mutations. / Zhang, H.; Reister Schultz, A.; Luty, S.; Rofelty, A.; Su, Y.; Means, S.; Bottomly, D.; Wilmot, Beth; McWeeney, Shannon; Tyner, Jeffrey.

In: Leukemia, Vol. 31, No. 12, 01.12.2017, p. 2752-2760.

Research output: Contribution to journalArticle

Zhang, H. ; Reister Schultz, A. ; Luty, S. ; Rofelty, A. ; Su, Y. ; Means, S. ; Bottomly, D. ; Wilmot, Beth ; McWeeney, Shannon ; Tyner, Jeffrey. / Characterization of the leukemogenic potential of distal cytoplasmic CSF3R truncation and missense mutations. In: Leukemia. 2017 ; Vol. 31, No. 12. pp. 2752-2760.
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