PU.1 Cooperates with IRF4 and IRF8 to Suppress Pre-B-cell Leukemia

Overview

Journal Leukemia

Specialties Hematology
Oncology

Date 2016 Mar 3

PMID 26932576

Citations 30

Authors

S H M Pang

M Minnich

P Gangatirkar

Z Zheng

A Ebert

G Song

R A Dickins

L M Corcoran

C G Mullighan

M Busslinger

N D Huntington

S L Nutt

S Carotta

Affiliations

Soon will be listed here.

Abstract

The Ets family transcription factor PU.1 and the interferon regulatory factor (IRF)4 and IRF8 regulate gene expression by binding to composite DNA sequences known as Ets/interferon consensus elements. Although all three factors are expressed from the onset of B-cell development, single deficiency of these factors in B-cell progenitors only mildly impacts on bone marrow B lymphopoiesis. Here we tested whether PU.1 cooperates with IRF factors in regulating early B-cell development. Lack of PU.1 and IRF4 resulted in a partial block in development the pre-B-cell stage. The combined deletion of PU.1 and IRF8 reduced recirculating B-cell numbers. Strikingly, all PU.1/IRF4 and ~50% of PU.1/IRF8 double deficient mice developed pre-B-cell acute lymphoblastic leukemia (B-ALL) associated with reduced expression of the established B-lineage tumor suppressor genes, Ikaros and Spi-B. These genes are directly regulated by PU.1/IRF4/IRF8, and restoration of Ikaros or Spi-B expression inhibited leukemic cell growth. In summary, we demonstrate that PU.1, IRF4 and IRF8 cooperate to regulate early B-cell development and to prevent pre-B-ALL formation.

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