Three‐way translocation involves MLL, MLLT3, and a novel cell cycle control gene, FLJ10374, in the pathogenesis of acute myeloid leukemia with t(9;11;19)(p22;q23;p13.3)

Abstract

The MLL gene, at 11q23, undergoes chromosomal translocation with a large number of partner genes in both acute lymphoblastic and acute myeloid leukemia (AML). We report a novel t(9;11;19)(p22;q23;p13.3) disrupting MLL in an infant AML patient. The 5' end of MLL fused to chromosome 9 sequences on the der(11), whereas the 3' end was translocated to chromosome 19. We developed long-distance inverse-polymerase chain reaction assays to investigate the localization of the breakpoints on der(11) and der(19). We found that intron 5 of MLL was fused to intron 5 of MLLT3 at the der(11) genomic breakpoint, resulting in a novel in-frame MLL exon 5-MLLT3 exon 6 fusion transcript. On the der(19), a novel gene annotated as FLJ10374 was disrupted by the breakpoint. Using reverse transcription-polymerase chain reaction analysis, we showed that FLJ10374 is ubiquitously expressed in human cells. Transfection of the FLJ10374 protein in different cell lines revealed that it localized exclusively to the nucleus. In serum-starved NIH-3T3 cells, the expression of FLJ10374 decreased the rate of the G1-to-S transition of the cell cycle, whereas the suppression of FLJ10374 through short interfering RNA increased cell proliferation. These results indicate that FLJ10374 negatively regulates cell cycle progression and proliferation. Thus, a single chromosomal rearrangement resulting in formation of the MLL-MLLT3 fusion gene and haplo-insufficiency of FLJ10374 may have cooperated to promote leukemogenesis in AML with t(9;11;19).

Complex and cryptic chromosomal rearrangements involving the MLL gene in acute leukemia: A study of 7 patients and review of the literature

“…Vieira et al (2006) identified all three fusion genes generated by a t(9;11;19)(p22;q23;p13.3) translocation [21]. The sole MLL-MLLT3 genomic fusion resulted in an in-frame transcript, as observed in the t(9;11) translocation.…”

Genomic analysis reveals recurrent deletion of JAK‐STAT signaling inhibitors HNRNPK and SOCS1 in mycosis fungoides

“…A total of 270 genes were found to be rearranged (Supporting Information Table 6), 47 of which are currently implicated in cancer (Supporting Information Table 7). This group includes genes previously associated with MF or Sézary Syndrome (SS) (ie, CDKN2A , CDKN2B , DLEU2 , KDM6A , TP53 , TP63 , and VAV1 ) and genes implicated in other hematological malignancies (eg, ARHGAP26 , CBFA2T3 , CHD2 , DOT1L , LCK , LPP , PBX1 , PTPN11 , MLLT3 , TAF15 , SPECC1 , ZMYM2 ) (Figure ) …”

Spliceosomal components protect embryonic neurons from R-loop-mediated DNA damage and apoptosis

“…On the basis of studies performed in human cell lines ( Paulsen et al, 2009 ), we hypothesized that elevated R-loop levels are driving the accumulation of DNA damage in the splicing factor mutants. R-loops were examined specifically in the sf3b1 hi3394aTg mutants for two reasons: firstly, because Sf3b1 is a core component of the spliceosome and, secondly, because Ccdc94, Sfpq and Plrg1 also have splicing-independent cellular functions that could potentially complicate the analysis of R-loops in their respective mutant lines ( Mahajan, 2016 ; An et al, 2014 ; Shav-Tal and Zipori, 2002 ; Berry and Gould, 1997 ; Legerski, 2009 ; Vieira et al, 2006 ). To measure cellular R-loop levels, immunofluorescence was performed using the S9.6 monoclonal antibody, which recognizes RNA:DNA hybrid structures ( Boguslawski et al, 1986 ).…”