Somatic SETBP1 mutations in myeloid neoplasms

Int J Hematol. 2017 Jun;105(6):732-742. doi: 10.1007/s12185-017-2241-1. Epub 2017 Apr 26.


SETBP1 is a SET-binding protein regulating self-renewal potential through HOXA-protein activation. Somatic SETBP1 mutations were identified by whole exome sequencing in several phenotypes of myelodysplastic/myeloproliferative neoplasms (MDS/MPN), including atypical chronic myeloid leukemia, chronic myelomonocytic leukemia, and juvenile myelomonocytic leukemia as well as in secondary acute myeloid leukemia (sAML). Surprisingly, its recurrent somatic activated mutations are located at the identical positions of germline mutations reported in congenital Schinzel-Giedion syndrome. In general, somatic SETBP1 mutations have a significant clinical impact on the outcome as poor prognostic factor, due to downstream HOXA-pathway as well as associated aggressive types of chromosomal defects (-7/del(7q) and i(17q)), which is consistent with wild-type SETBP1 activation in aggressive types of acute myeloid leukemia and leukemic evolution. Biologically, mutant SETBP1 attenuates RUNX1 and activates MYB. The studies of mouse models confirmed biological significance of SETBP1 mutations in myeloid leukemogenesis, particularly associated with ASXL1 mutations. SETBP1 is a major oncogene in myeloid neoplasms, which cooperates with various genetic events and causes distinct phenotypes of MDS/MPN and sAML.

Keywords: Myelodysplastic/myeloproliferative neoplasms; Poor prognosis; SETBP1; Secondary acute myeloid leukemia; Self-renewal potential.

Publication types

  • Review

MeSH terms

  • Animals
  • Carrier Proteins* / genetics
  • Carrier Proteins* / metabolism
  • Chromosome Deletion*
  • Chromosomes, Human, Pair 7 / genetics
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Humans
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / metabolism
  • Leukemia, Myeloid, Acute* / mortality
  • Leukemia, Myeloid, Acute* / therapy
  • Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative* / genetics
  • Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative* / metabolism
  • Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative* / mortality
  • Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative* / therapy
  • Leukemia, Myelomonocytic, Chronic* / genetics
  • Leukemia, Myelomonocytic, Chronic* / metabolism
  • Leukemia, Myelomonocytic, Chronic* / mortality
  • Leukemia, Myelomonocytic, Chronic* / therapy
  • Leukemia, Myelomonocytic, Juvenile*
  • Mice
  • Nuclear Proteins* / genetics
  • Nuclear Proteins* / metabolism
  • Proto-Oncogene Proteins c-myb / genetics
  • Proto-Oncogene Proteins c-myb / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism


  • ASXL1 protein, human
  • Asxl1 protein, mouse
  • Carrier Proteins
  • Core Binding Factor Alpha 2 Subunit
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-myb
  • RUNX1 protein, human
  • Repressor Proteins
  • Runx1 protein, mouse
  • SETBP1 protein, human
  • Setbp1 protein, mouse