Point mutation in AML1 disrupts subnuclear targeting, prevents myeloid differentiation, and effects a transformation-like phenotype

Diana Vradii, Sayyed K. Zaidi, Jane B. Lian, Andre J van Wijnen, Janet L. Stein, Gary S. Stein

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The multifunctional C terminus of the hematopoietic AML1 transcription factor interacts with coregulatory proteins, supports the convergence and integration of physiological signals, and contains the nuclear matrix targeting signal, the protein motif that is necessary and sufficient to target AML1 to subnuclear sites. The (8;21) chromosomal translocation, which replaces the C terminus of AML1 with the ETO protein, modifies subnuclear targeting of AML1 in acute myeloid leukemia (AML) and results in defective myelopoiesis. We therefore addressed the relevance of AML1 subnuclear targeting and associated functions that reside in the C terminus to myeloid differentiation. A single amino acid substitution that abrogates intranuclear localization was introduced in the AML1 subnuclear targeting signal. Expression of the mutant AML1 protein blocks differentiation of myeloid progenitors to granulocytes in the presence of endogenous AML1 protein, as also occurs in the (8;21) chromosomal translocation, where only one allele of the AML1 gene is affected. The cells expressing the mutant AML1 protein continue to proliferate, maintain an immature blast-like morphology, and exhibit transformed properties that are hallmarks of leukemogenesis. These findings functionally link AML1 subnuclear targeting with competency for myeloid differentiation and expression of the transformed/leukemia phenotype.

Original languageEnglish (US)
Pages (from-to)7174-7179
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number20
DOIs
StatePublished - May 17 2005
Externally publishedYes

Fingerprint

Point Mutation
Genetic Translocation
Mutant Proteins
Phenotype
Myelopoiesis
Nuclear Matrix
Granulocyte Precursor Cells
Amino Acid Motifs
Proteins
Amino Acid Substitution
Acute Myeloid Leukemia
Leukemia
Transcription Factors
Alleles
Genes

Keywords

  • Acute myeloid leukemia
  • AML1-ETO fusion protein
  • Nuclear matrix
  • Subnuclear organization

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Point mutation in AML1 disrupts subnuclear targeting, prevents myeloid differentiation, and effects a transformation-like phenotype. / Vradii, Diana; Zaidi, Sayyed K.; Lian, Jane B.; van Wijnen, Andre J; Stein, Janet L.; Stein, Gary S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 20, 17.05.2005, p. 7174-7179.

Research output: Contribution to journalArticle

Vradii, Diana ; Zaidi, Sayyed K. ; Lian, Jane B. ; van Wijnen, Andre J ; Stein, Janet L. ; Stein, Gary S. / Point mutation in AML1 disrupts subnuclear targeting, prevents myeloid differentiation, and effects a transformation-like phenotype. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 20. pp. 7174-7179.
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