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The t(8;21) translocation between two genes known as AML1 and ETO is seen in approximately 12-15% of all acute myeloid leukemia (AML) and is the second-mostfrequently observed nonrandom genetic alteration associated with AML. AML1 up-regulates a number of target genes critical to normal hematopoiesis, whereas the AML1͞ETO fusion interferes with this trans-activation. We discovered that the fusion partner ETO binds to the human homolog of the murine nuclear receptor corepressor (N-CoR). The interaction is mediated by two unusual zinc finger motifs present at the carboxyl terminus of ETO. Human N-CoR (HuN-CoR), which we cloned and sequenced in its entirety, encodes a 2,440-amino acid polypeptide and has a central domain that binds ETO. N-CoR, mammalian Sin3 (mSin3A and B), and histone deacetylase 1 (HDAC1) form a complex that alters chromatin structure and mediates transcriptional repression by nuclear receptors and by a number of oncoregulatory proteins. We found that ETO, through its interaction with the N-CoR͞mSin3͞HDAC1 complex, is also a potent repressor of transcription. This observation provides a mechanism for how the AML1͞ETO fusion may inhibit expression of AML1-responsive target genes and disturb normal hematopoiesis.

To study the role of a nuclear proto-oncogene in the regulation of cell growth and differentiation, we inhibited HL-60 c-myc expression with a complementary antisense oligomer. This oligomer was stable in culture and entered cells, forming an intracellular duplex. Incubation of cells with the anti-myc oligomer decreased the steady-state levels of c-myc protein by 50 to 80%, whereas a control oligomer did not significantly affect the c-myc protein concentration. Direct inhibition of c-myc expression with the anti-myc oligomer was associated with a decreased cell growth rate and an induction of myeloid differentiation. Related antisense oligomers with 2-to 12-base-pair mismatches with c-myc mRNA did not influence HL-60 cells. Thus, the effects of the antisense oligomer exhibited sequence specificity, and furthermore, these effects could be reversed by hybridization competition with another complementary oligomer. Antisense inhibition of a nuclear protooncogene apparently bypasses cell surface events in affecting cell proliferation and differentiation.The molecular mechanisms that regulate cellular proliferation and differentiation involve signal transduction from membrane receptors to events that are mediated by nuclear proteins (4, 5). Candidates for such regulatory proteins include the following members of the nuclear proto-oncogene family: c-myc, N-myc, c-myb, p53, c-fos, c-ski (for a review, see reference 54). The evidence that implicates these genes in growth control is the observation that their mutated forms produce dysregulated growth in vitro, such as immortalization, which can be assayed by transformation of primary embryo fibroblasts in cooperation with activated ras oncogenes (29,33,42,48), and in vivo, such as in tumors in transgenic mice (1,33,46,51) or patients with Burkitt lymphoma (for reviews, see references 28 and 31).The c-myc gene has a higher level of expression in proliferating cells than in differentiated cells (for reviews, see references 9 and 54). Gene transfer experiments have demonstrated that constitutive expression of c-myc inhibits induced differentiation of cell lines (12,14,32,43,47), supporting the fact that there is an inverse association between c-myc expression and differentiation, although exceptions have been reported (15,16,49). Dysregulated c-myc expression perturbs lymphocyte differentiation during embryonic development in transgenic mice (34) and contributes to tumor development in adult animals (1, 35).HL-60 promyelocytic leukemia cells (11, 21) represent a useful model system for studying the role of proto-oncogenes in cellular proliferation and differentiation (54). Several mutations in specific proto-oncogenes have been identified in HL-60 cells that may account for the transformed phenotype (39). The c-myc gene is amplified 8-to 30-fold and is highly expressed (10, 13); this is in association with an activated N-ras gene (39) and deletion of another nuclear oncogene, p53 (58). Because both p53 and c-myc transform primary embryo fibroblasts in cooperation with activa...

The t(15;17)(q22;q21) translocation is tightly linked to the APL phenotype, and the resultant PML-RAR fusion can be demonstrated in 98% of APL cases. Rare variant translocations have been reported, the majority of which on detailed analysis represent cryptic PML-RAR fusions. However, a handful of APL cases have been described with different genotypes. These include the t(11;17)(q23;q21) that produces the PLZF-RAR fusion, t(5;17)(q35;q21) that forms NPM-RAR, t(11;17)(q13;q21) that generates NUMA-RAR, and der(17) that creates STAT5b-RAR. In this review we will discuss these variant translocations, and discuss the insights that we have gained from their study.

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