The Wilms tumor suppressor WT1 directs stage-specific quiescence and differentiation of human hematopoietic progenitor cells

Leif W. Ellisen, Nadia Carlesso, Tao Cheng, David T. Scadden, Daniel A. Haber

Research output: Contribution to journalArticle

130 Citations (Scopus)

Abstract

WT1, a transcription factor implicated in both normal kidney differentiation and tumorigenesis, is also expressed in differentiating hematopoietic progenitors. Most human acute leukemias contain high levels of the wild-type transcript, while a minority have point mutations, raising the possibility that this tumor suppressor might have a paradoxical oncogenic effect in some hematopoietic cells. Using high titer retroviral infection, we demonstrate that WT1 triggers rapid growth arrest and lineage-specific differentiation in primary hematopoietic progenitors and differentiation-competent leukemia cell lines, while it induces cellular quiescence in a primitive subset of primary precursors. Growth arrest by WT1 is associated with induction of p21CIPI but expression of this cyclin-dependent kinase inhibitor alone is insufficient for either cellular differentiation or primitive cell preservation. The effects of WT1 are enhanced by coexpression of its naturally occurring isoforms, and are correlated with the physiological expression pattern of WT1 in vivo. Our observations suggest a role for WT1 in the differentiation of human hematopoietic cells, and provide a functional model that supports its capacity as a tumor suppressor in human acute leukemia.

Original languageEnglish (US)
Pages (from-to)1897-1909
Number of pages13
JournalEMBO Journal
Volume20
Issue number8
DOIs
StatePublished - Apr 17 2001
Externally publishedYes

Fingerprint

Wilms Tumor
Hematopoietic Stem Cells
Tumors
Leukemia
Cells
Cyclin-Dependent Kinases
Protein Isoforms
Transcription Factors
Growth
Point Mutation
Neoplasms
Carcinogenesis
Kidney
Cell Line
Infection

Keywords

  • Hematopoiesis
  • Leukemia
  • Tumor suppressor
  • WT1

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

The Wilms tumor suppressor WT1 directs stage-specific quiescence and differentiation of human hematopoietic progenitor cells. / Ellisen, Leif W.; Carlesso, Nadia; Cheng, Tao; Scadden, David T.; Haber, Daniel A.

In: EMBO Journal, Vol. 20, No. 8, 17.04.2001, p. 1897-1909.

Research output: Contribution to journalArticle

Ellisen, Leif W. ; Carlesso, Nadia ; Cheng, Tao ; Scadden, David T. ; Haber, Daniel A. / The Wilms tumor suppressor WT1 directs stage-specific quiescence and differentiation of human hematopoietic progenitor cells. In: EMBO Journal. 2001 ; Vol. 20, No. 8. pp. 1897-1909.
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