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REMANIEMENTS DU GENE NUP98 DANS LES HEMOPATHIES MALIGNES HUMAINES

Arnaud Petit 1
1 INSERM
EMI0210 - INSERM EMI0210
Abstract : The human malignant hemopathies are associated with recurrent chromosomal rearrangements. NUP98 is a multipartners gene, rearranged in a recurring way in the malignant hemopathies. It codes for a nucleoporin which participates in the complex of nuclear pore. Two new partners CCDC28A in 6q24 and HMGB3 in Xq28 were characterized in two patients presenting a malignant hemopathy with NUP98 rearrangement. A NUP98-NDS1 fusion is described in a complex translocation. A retrospective review of the published cases indicates that NUP98 rearrangements are rare. They arise essentially in de novo myeloid hemopathies, sometimes in T acute lymphoblastic leukemia, never in B acute lymphoblastic leukemia. The partner genes include homeobox genes, genes reshaping the chromatin and genes coding for cytoplasmic proteins. In proportion, the partners most frequently rearranged are the HOX genes. Hemopathies are always with simple karyotypes. There is a correlation between genotype and phenotype. The protein CCDC28A, of unknown function, is of cytoplasmic localization. A similar protein, CCDC28B, is involved in genetics human, in the syndrome of Bardet-Biedl. Transcript CCDC28A is prematurely expressed during embryogenesis and in all the human tissues. HMGB3 is a gene of the murine hematopoiesis and the embryonic stem cells. The functional study of the NUP98-CCDC28A and NUP98-HMGB3 fusions, in murine hematopoietic progenitors, transplanted to irradiated mice, showed their strong transformants powers. These fusions lead quickly lethal acute leukemias. In an original way, these fusions deregulate little the HOX, and do not deregulate MEIS1, contrary to several fusions NUP98, in particular NUP98-HOXA9, suggesting a different mechanism of transformation, situated downstream to the canonical Hoxa9-Meis1 pathway.
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Arnaud Petit. REMANIEMENTS DU GENE NUP98 DANS LES HEMOPATHIES MALIGNES HUMAINES. Cancer. Université Paris-Diderot - Paris VII, 2010. Français. ⟨NNT : 2010PA077086⟩. ⟨tel-00649445⟩

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