Recurrent coiled-coil motifs in NUP98 fusion partners provide a clue to leukemogenesis

DJ Hussey, A Dobrovic - Blood, The Journal of the American …, 2002 - ashpublications.org
Blood, The Journal of the American Society of Hematology, 2002ashpublications.org
The NUP98 gene is the target of recurrent translocations in leukemia that fuse the 5 portion
of NUP98 with coding sequence from the partner gene. 1-8 Three of the known fusion
partners, HOXA9, HOXD13, and PMX1, are homeobox genes. The other known fusion
partners, DDX10, RAP1GDS1, TOP1, and LEDGF, are considered to share no common
features. Recently NSD1, another nonhomeobox NUP98 fusion partner, has been reported
in this journal. 8 We now report that the proteins coded for by the nonhomeobox genes all …
The NUP98 gene is the target of recurrent translocations in leukemia that fuse the 5 portion of NUP98 with coding sequence from the partner gene. 1-8 Three of the known fusion partners, HOXA9, HOXD13, and PMX1, are homeobox genes. The other known fusion partners, DDX10, RAP1GDS1, TOP1, and LEDGF, are considered to share no common features. Recently NSD1, another nonhomeobox NUP98 fusion partner, has been reported in this journal. 8 We now report that the proteins coded for by the nonhomeobox genes all have regions with a significant probability of adopting a coiled-coil conformation. Oligomerization via the coiled-coil domains has recently been shown to activate the oncogenic potential of RAR and AML1 following fusion to partners with coiled-coil domains. 9 It was shown that the PML-RAR, PLZF-RAR, NPM-RAR, and AML1-ETO fusion proteins each exist in oligomeric complexes in vivo and that oligomerization causes abnormal recruitment of the transcriptional corepressor N-CoR. Moreover, fusion of RAR to the oligomerization domain of p53 showed that oligomerization alone is sufficient for transformation. Other leukemia fusion genes also involve the fusion of transcription factors with genes coding for coiled-coil domains. For example, the inv (16)(p13q22) fuses the N-terminus of CBF with the C-terminus of the smooth muscle myosin heavy-chain gene. 10 The coiled-coils of the myosin heavychain gene promote dimerization and are essential for the transforming properties of the fusion gene. 11 Coiled-coils are characterized by sequence patterns known as heptad repeats, which result in the formation of amphipathic alpha helices, the hydrophobic faces of which undergo what is known as “knobs-into-holes packing” as first proposed by Crick. 12 Potential coiled-coil forming sequences were sought using both algorithms in COILS 2.1 (http://www. ch. embnet. org/software/COILS_form. html). The original algorithm of Lupas et al gives equal weighting
ashpublications.org