Point mutation in AML1 disrupts subnuclear targeting, prevents myeloid differentiation, and effects a transformation-like phenotype.
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.
Vradii
Diana
D
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
Zaidi
Sayyed K
SK
Lian
Jane B
JB
van Wijnen
Andre J
AJ
Stein
Janet L
JL
Stein
Gary S
GS
D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D002458:Cell Fractionation; D002460:Cell Line; D002467:Cell Nucleus / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003114:Colony-Forming Units Assay; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007951:Leukemia, Myeloid / Q000235:genetics*; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014161:Transduction, Genetic
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C493726:Runx1 protein, mouse; D014157:Transcription Factors; D009195:Peroxidase