Journal Article

A retroviral library genetic screen identifies IRF-2 as an inhibitor of N-ras-induced growth suppression in leukemic cells

Dolnikov, Alla, Passioura, Toby, Symonds, Geoff, Shen, Sylvie

2005

Overview

Activating mutations of the N-ras gene occur at relatively high frequency in acute myeloid leukemia and myelodysplastic syndrome. Somewhat paradoxically, ectopic expression of activated N-ras in primary hematopoietic cells and myeloid cell lines (in some cases) can lead to inhibition of proliferation. Expression of mutant N-ras in murine hematopoietic stem/progenitor cells is sufficient to induce myeloid malignancies, but these pathologies occur with long latency. This suggests that mutations that disable the growth suppressive properties of N-ras in hematopoietic cells are required for the development of frank malignancy. In the present work, the growth suppression induced by a mutant N-ras gene in U937 myeloid cells was used as the basis to screen a retroviral cDNA library for genes that prevent mutant N-ras -induced growth suppression (i.e., putative cooperating oncogenes). This screen identified the gene for the transcription factor interferon regulatory factor-2 (IRF-2), and as confirmation of the screen, overexpression of this gene in U937 cells was shown to inhibit mutant N-ras -induced growth suppression. Also recovered from the screen were two truncated clones of an uncharacterized gene (interim official symbol: PP2135 ). Overexpression of this truncated PP2135 gene in U937 cells did not appear to abrogate mutant N-ras -induced growth suppression, but rather appeared to confer an increased sensitivity of U937 cells to retroviral infection, accounting for the recovery of this gene from the genetic screen.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Acute myeloid leukemia / Apoptosis / Biological and medical sciences / Blotting, Northern / Bone marrow / Cell Biology / Cell physiology / Cell Proliferation / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Cloning / Cooperation / Ectopic expression / Fundamental and applied biological sciences. Psychology / Gene Expression / Gene Library / Genes / Genes, ras - physiology / Genetic screening / Hematologic and hematopoietic diseases / Hematopoietic stem cells / Human Genetics / Humans / Infections / Interferon / Interferon regulatory factor / Interferon Regulatory Factor-2 - physiology / Internal Medicine / Latency / Leukemia / Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis / Malignancy / Medical sciences / Medicine / Medicine & Public Health / Molecular and cellular biology / Mutants / Mutation / Mutation - genetics / Myelodysplastic syndrome / Myelodysplastic syndromes / Myeloid cells / N-ras gene / Oncology / original-paper / Polymerase Chain Reaction / Progenitor cells / Ras protein / Retroviridae - genetics / Transcription factors / U937 Cells - cytology / U937 Cells - metabolism