NUP98 rearrangements in hematopoietic malignancies: a study of the Groupe Francophone de Cytogénétique Hématologique.

The NUP98 gene is fused with 19 different partner genes in various human hematopoietic malignancies. In order to gain additional clinico-hematological data and to identify new partners of NUP98, the Groupe Francophone de Cytogénétique Hématologique (GFCH) collected cases of hematological malignancies where a 11p15 rearrangement was detected. Fluorescence in situ hybridization (FISH) analysis showed that 35% of these patients (23/66) carried a rearrangement of the NUP98 locus. Genes of the HOXA cluster and the nuclear-receptor set domain (NSD) genes were frequently fused to NUP98, mainly in de novo myeloid malignancies whereas the DDX10 and TOP1 genes were equally rearranged in de novo and in therapy-related myeloid proliferations. Involvement of ADD3 and C6ORF80 genes were detected, respectively, in myeloid disorders and in T-cell acute lymphoblastic leukemia (T-ALL), whereas the RAP1GDS1 gene was fused to NUP98 in T-ALL. Three new chromosomal breakpoints: 3q22.1, 7p15 (in a localization distinct from the HOXA locus) and Xq28 were detected in rearrangements with the NUP98 gene locus. The present study as well as a review of the 73 cases previously reported in the literature allowed us to delineate some chromosomal, clinical and molecular features of patients carrying a NUP98 gene rearrangements.     

The role of NUP98 gene fusions in hematologic malignancy

Chromosomal aberrations occur with great frequency and some specificity in leukemia and other hematologic malignancies. The most common outcome of these rearrangements is the formation of a fusion gene, comprising portions of 2 genes normally present in the cell. These fusion proteins are presumed to be oncogenic; in many cases, animal models have proven them to be oncogenic. One of the most promiscuous fusion partner genes is the newly identified NUP98 gene, located on chromosome 11p15.5, which to date has been observed fused to 15 different fusion partners. NUP98 encodes a 98 kD protein that is an important component of the nuclear pore complex, which mediates nucleo-cytoplasmic transport of protein and RNA. The fusion partners of NUP98 form 2 distinct groups: homeobox genes and non-homeobox genes. All NUP98 fusions join the N-terminal GLFG repeats of NUP98 to the C-terminal portion of the partner gene, which, in the case of the homeobox gene partners, includes the homeodomain. Clinical findings are reviewed here, along with the findings of several in vivo and in vitro models have been employed to investigate the mechanisms by which NUP98 fusion genes contribute to the pathogenesis of leukemia.     

非典型急性早幼粒细胞白血病1例病案报道及文献复习

目的:报道一例非典型急性早幼粒细胞白血病(APL),阐明Inv(11)(p15q22)相关非典型APL的临床遗传学特点,初步探究NUP98基因在白血病发病中的作用机制。方法:对该APL患者采用骨髓直接法和24小时培养法制备染色体,应用R显带技术进行核型分析。结果:R显带分析显示46,xy,inv(11)(p15q22)。结论:Inv(11)(p15q22)可导致非典型APL发病。     

The t(8;9)(p22;p24) translocation in atypical chronic myeloid leukaemia yields a new PCM1-JAK2 fusion gene

Several tyrosine kinase genes are involved in chromosomal translocations in chronic myeloproliferative disorders, but there are still uncharacterized translocations in some cases. We report two such cases corresponding to atypical chronic myeloid leukaemia with a t(8;9)(p22;p24) translocation. By fluorescence in situ hybridisation (FISH) on the corresponding metaphases with a bacterial artificial chromosome probe encompassing the janus kinase 2 (JAK2) gene at 9p24, we observed a split for both patients, suggesting that this gene was rearranged. The locus at 8p22 contains different candidate genes including the pericentriolar material 1 gene (PCM1), already implicated in reciprocal translocations. The rearrangement of the PCM1 gene was demonstrated by FISH, for both patients. By RT-PCR, we confirmed the fusion of 3' part of JAK2 with the 5' part of PCM1. Sequence analysis of the chimeric PCM1-JAK2 mRNA suggests that the putative protein displays the coiled-coil domains of PCM1 and the tyrosine kinase domain of JAK2. This new translocation identifies JAK2 as a possible therapeutic target for compounds with anti-tyrosine kinase activity.     

非典型急性早幼粒细胞白血病1例病案报道及文献复习

目的：报道一例非典型急性早幼粒细胞白血病（APL）,阐明Inv（11）（p15q22）相关非典型APL的临床遗传学特点,初步探究NUP98基因在白血病发病中的作用机制。方法：对该APL患者采用骨髓直接法和24小时培养法制备染色体,应用R显带技术进行核型分析。结果：R显带分析显示46,xy,inv（11）（p15q22）。结论：Inv（11）（p15q22）可导致非典型APL发病。     

t(11;14)(q23;q24) generates an MLL-human gephyrin fusion gene along with a de facto truncated MLL in acute monoblastic leukemia

More than 20 different partner genes with MLL have been cloned from leukemia cells with translocations involving chromosome 11 band q23 (11q23). All reported partner genes fused in-frame to MLL and the fusion cDNA encode chimeric MLL proteins with a significant portion derived from the partner genes. We analyzed one patient with de novo acute monoblastic leukemia with t(11;14)(q23;q24) and identified that a human homologue of gephyrin (human gephyrin) fused with MLL. Gephyrin is a rat glycine receptor-associated protein, which forms submembranous complexes and anchor glycine or gamma-aminobutyric acidA receptors to microtubules. Alternative splicing of human gephyrin gene created two different forms of fusion cDNA. In one form, human gephyrin gene fused in-frame to MLL exon 9, and the chimeric product had COOH terminus of human gephyrin protein, including the tubulin binding site. In the other, the reading frame terminated shortly after the fusion point. As a result, only seven amino acids with no known function were attached to the NH2 terminus of MLL protein. The functional significance of this de facto truncated MLL gene product is not clear.     

Rearrangement of MLL in a patient with congenital acute monoblastic leukemia and granulocytic sarcoma associated with a t(1;11)(p36;q23) translocation

Band 11q23 is known to be involved in translocations and insertions with a variety of partner chromosomes. In most cases, they lead to MLL rearrangements, resulting in a fusion with numerous genes. We report here a newborn girl who had disseminated intravascular coagulation and cutaneous tumors (granulocytic sarcomata) in whom a diagnosis of acute myeloblastic leukemia (AML) FAB-M5 was made. Conventional cytogenetics using R-banding showed 11 of the 17 metaphases observed to have a 46,XX,t(1;11)(p36.2;q23) karyotype. FISH analysis confirmed the disruption of the MLL gene. Two adult patients solely have been found to have a t(1;11)(p36;q23); however, no FISH analysis with a MLL probe was performed in both cases. Since the diagnosis was made at birth, this implies that the MLL rearrangement and the onset of the disease occurred in utero. Twenty children, including 3 newborns, have been reported to have granulocytic sarcoma associated with 11q23/MLL rearrangement. To the best of our knowledge, this is the first report of a case of congenital AML with GS arising in a patient with proven MLL rearrangement.