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The lineage-determining transcription factor CCAAT enhancer binding protein [alpha] (C/EBP[alpha]) is required for myeloid differentiation. Decreased function or expression of C/EBP[alpha] is often found in human acute myeloid leukemia. However, the precise impact of C/EBP[alpha] deficiency on the maturation arrest in leukemogenesis is not well understood. To address this question, we used a murine transplantation model of a bcr/abl-induced myeloproliferative disease. The expression of bcr/abl in C/EBP[[alpha].sup.Pos] fetal liver cells led to a chronic myeloid leukemia-like disease. Surprisingly, bcr/abl-expressing C/EBP[[alpha].sup.-/-] fetal liver cells failed to induce a myeloid disease in transplanted mice, but caused a fatal, transplantable erythroleukemia instead. Accordingly, increased expression of the transcription factors SCL and GATA-1 in hematopoietic precursor cells of C/EBP[[alpha].sup.-/-] fetal livers was found. The mechanism for the lineage shift from myeloid to erythroid leukemia was studied in a bcr/abl-positive cell line. Consistent with findings of the transplant model, expression of C/EBP[alpha] and GATA-1 was inversely correlated. Id1, an inhibitor of erythroid differentiation, was identified as a critical direct target of C/EBP[alpha]. Down-regulation of Id1 by RNA interference impaired C/EBP[alpha]-induced granulocytic differentiation. Taken together, our study provides evidence that myeloid lineage identity of malignant hematopoietic progenitor cells requires the residual expression of C/EBP[alpha]. differentiation | leukemia | lineage commitment

Interferon consensus sequence binding protein (ICSBP)-mutant mice were analyzed to determine the role of ICSBP in the antiviral responses of the immune system and chronic myelogenous leukemia (CML). ICSBP mutants exhibited normal antiviral responses to vesicular stomatitis virus indicating that the interferon, B and T lymphocytic system was not altered by ICSBP- deficiency. However, the mutant mice died after being infected with the lymphocytic choriomeningitis virus. Furthermore, the mutants exhibited hematologic neoplasia that is characteristic of CML.

A study was conducted to show noncoding antisense RNAs as an important modulators of proper dosages of PU.1, regulator of hematopoiesis critical for normal hematopoietic development and suppression of leukemia. The results showed that antisense transcripts serve to keep the levels of PU.1 from becoming too high in expression cells by modulating mRNA translation.