HoxB8 requires its Pbx-interaction motif to block differentiation of primary myeloid progenitors and of most cell line models of myeloid differentiation

Paul S Knoepfler, David B. Sykes, Martina Pasillas, Mark P. Kamps

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

HoxB8 was the first homeobox gene identified as a cause of leukemia. In murine WEHI3B acute myeloid leukemia (AML) cells, proviral integration leads to the expression of both HoxB8 and Interleukin (IL-3). Enforced expression of HoxB8 blocks differentiation of factor-dependent myeloid progenitors, while IL-3 co-expression induces autocrine proliferation and overt leukemogenicity. Previously, we demonstrated that HoxB8 binds DNA cooperatively with members of the Pbx family of transcription factors, and that HoxB8 makes contact with the Pbx homeodomain through a hexameric sequence designated the Pbx-interaction motif (PIM). E2a-Pbx1, an oncogenic derivative of Pbx1, both retains its ability to heterodimerize with Hox proteins and arrest myeloid differentiation. This observation prompts the question of whether E2a-Pbx1 and Hox oncoproteins use endogenous Hox and Pbx proteins, respectively, to target a common set of cellular genes. Here, we use four different models of neutrophil and macrophage differentiation to determine whether HoxB8 needs to bind DNA or Pbx cofactors in order to arrest myeloid differentiation. The ability of HoxB8 to bind DNA or to bind Pbx was essential (1) to block differentiation of factor-dependent myeloid progenitors from primary marrow; (2) to block IL-6-induced monocytic differentiation of M1-AML cells; and (3) to block granulocytic differentiation of GM-CSF-dependent ECoM-G cells. However, while DNA-binding was required, the HoxB8 Pbx-interaction motif was unnecessary for preventing macrophage differentiation of ECoM-M cells. We conclude that HoxB8 prevents differentiation by directly influencing cellular gene expression, and that the genetic context within a cell dictates whether the effect of HoxB8 is dependent on a physical interaction with Pbx proteins.

Original languageEnglish (US)
Pages (from-to)5440-5448
Number of pages9
JournalOncogene
Volume20
Issue number39
DOIs
StatePublished - Sep 6 2001
Externally publishedYes

Fingerprint

Myeloid Progenitor Cells
Interleukin-3
Cell Line
Aptitude
DNA
Myeloid Cells
Macrophages
Gastrin-Secreting Cells
Proteins
Homeobox Genes
Oncogene Proteins
Granulocyte-Macrophage Colony-Stimulating Factor
Acute Myeloid Leukemia
Interleukin-6
Leukemia
Neutrophils
Transcription Factors
Bone Marrow
Gene Expression
Genes

Keywords

  • Differentiation
  • HoxB8
  • Myeloid
  • Pbx

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

HoxB8 requires its Pbx-interaction motif to block differentiation of primary myeloid progenitors and of most cell line models of myeloid differentiation. / Knoepfler, Paul S; Sykes, David B.; Pasillas, Martina; Kamps, Mark P.

In: Oncogene, Vol. 20, No. 39, 06.09.2001, p. 5440-5448.

Research output: Contribution to journalArticle

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