HOX genes, notably members of the HOXA cluster, and HOX cofactors have increasingly been linked to human leukemia. Intriguingly, HOXD13, a member of the HOXD cluster not normally expressed in hematopoietic cells, was recently identified as a partner of NUP98 in a t(2;11) translocation associated with t-AML/MDS. We have now tested directly the leukemogenic potential of the NUP98-HOXD13 t (

Rehovot 76100, Israel chains have been identified: IFNAR1 (Uze et al., 1990) 1 Corresponding author and IFNAR2-2 (or IFNAR2-c, Domanski et al., 1995;Lutfalla et al., 1995), which is a long form of IFN-α/βR The intracytoplasmic domain (IC) of cytokine receptors (Novick et al., 1994). Transduction of the signal generated provides docking sites for proteins which mediate by IFN-α,β,ω involves protein tyrosine kinases of the signal transduction. Thus, in interferon-α,β receptors Janus kinases (Jak) family and transcription factors of the (IFNAR1 and 2), the IC region binds protein-tyrosine Stat family (Velazquez et al., 1992;Darnell et al., 1994). and -serine/threonine kinases which phosphorylate the Proteins of the Jak-Stat pathways have been shown to receptor and the associated Stat transcription factors.bind to the intracytoplasmic (IC) domains of the IFNAR1 A two-hybrid screening was carried out to identify and 2 receptor chains. Jak1 is constitutively associated additional proteins which could interact with the IC with IFNAR2 (Novick et al., 1994), whereas tyk2 is bound domain of the IFNAR1 chain of the IFN-α,β receptor.to the IC domain of IFNAR1 (Abramovich et al., 1994b; Several positive clones representing a protein sequence Colaminici et al., 1994). IFNAR1 can also bind Stat2 (Abramovich et al., 1994b), and the docking site for latent designated IR1B4 were recovered from a human cDNA Stat2 was identified as a peptide containing phosphotyrolibrary. IR1B4 was identified as the human homolog sine Y466, adjacent to the tyk2 binding site (amino acids of PRMT1, a protein-arginine methyltransferase from 479-511) in the 100 amino acid long IFNAR1-IC region rat cells. Flag-IR1B4 fusion proteins bind to the isolated (Yan et al., 1996). IC was observed . Protein-tyrosine antibodies from untreated human cells. IR1B4/PRMT1 phosphatases PTP1C and D reversibly associate with is involved in IFN action since U266 cells rendered IFNAR1 upon IFN addition (David et al., 1995a). In deficient in this methyltransferase by antisense oligonuaddition, two serine/threonine protein kinases, the 48 kDa cleotides become more resistant to growth inhibition ERK2 MAP kinase (David et al., 1995b) and the cAMPby IFN. Methylation of proteins by enzymes which can activated protein kinase A (PKA; David et al., 1996) attach to the IC domains of receptors may be a signaling bind to the isolated membrane-proximal 50 residues of mechanism complementing protein phosphorylation.IFNAR1-IC. Therefore, the IC domains of type I IFN Among substrates methylated by PRMT1 are RNAreceptors serve as docking sites for multiple proteins binding heterogeneous nuclear ribonucleoproteins involved in phosphorylation and dephosphorylation. Both (hnRNPs) which are involved in mRNA processing, IFNAR1 and IFNAR2 become tyrosine phosphorylated in splicing and transport into the cytoplasm.response to IFN treatment, and binding of a tyrosineKeywords: interferon/methyltransferase/protein phosphorylated protein (βPTyr) to IFNAR1 is seen spemethylation/receptor/signaling cif...

NUP98-Hox fusion genes are newly identified oncogenes isolated in myeloid leukemias. Intriguingly, onlyAbd-B Hox genes have been reported as fusion partners, indicating that they may have unique overlapping leukemogenic properties. To address this hypothesis, we engineered novel NUP98 fusions with Hox genes not previously identified as fusion partners: the Abd-B-like gene HOXA10 and two Antennepedia-like genes, HOXB3 and HOXB4. Notably, NUP98-HOXA10 and NUP98-HOXB3 but not NUP98-HOXB4 induced leukemia in a murine transplant model, which is consistent with the reported leukemogenic potential ability of HOXA10 and HOXB3 but not HOXB4. Thus, the ability of Hox genes to induce leukemia as NUP98 fusion partners, although apparently redundant for Abd-B-like activity, is not restricted to this group, but rather is determined by the intrinsic leukemogenic potential of the Hox partner. We also show that the potent leukemogenic activity of Abd-B-like Hox genes is correlated with their strong ability to block hematopoietic differentiation. Conversely, coexpression of the Hox cofactor Meis1 alleviated the requirement of a strong intrinsic Hox-transforming potential to induce leukemia. Our results support a model in which many if not all Hox genes can be leukemogenic and point to striking functional overlap not previously appreciated, presumably reflecting common regulated pathways.