An MLL-SEPT9 fusion and t(11;17)(q23;q25) associated with de novo myelodysplastic syndrome

Abstract

Rearrangements of the MLL gene at chromosome 11q23 are uncommon in de novo myelodysplastic syndrome (MDS). Here we describe molecular findings in a patient with multilineage dysplasia and t(11;17)(q23;q25) who responded to decitabine therapy. Fluorescent in situ hybridization (FISH) demonstrated rearrangement of MLL, while RT-PCR analysis and sequencing identified the transcript fusion partner as SEPT9, a member of the septin family of GTPases. MLL-SEPT9 fusion appears to be rare, having been described to date in only 7 cases of AML and not, to our knowledge, in MDS. Analysis of MLL-septin family member fusion products such as the one seen here may provide further insights into the etiology of myeloid neoplasia, and MLL-SEPT9 fusion may be worth seeking in other cases of MLL rearrangements with a translocation partner on chromosome 17q.

Septin roles in tumorigenesis

“…Gene fusion AML (Ono et al, 2002;Kadkol et al, 2006;Cerveira et al, 2008) Melanoma (Jaeger et al, 2007) SEPT7 Downregulation Glioma (Nagata et al, 2000;Jiang, 2002;Jiang, 2004;Jia et al, 2010;Tanaka et al, 2010) SEPT8 None None None SEPT9 Amplification/ Breast (Montagna et al, 2003;Scott et al, 2005;overexpression Gonzalez et al, 2007overexpression Gonzalez et al, , 2009) Upregulation Ovary Gene fusion AML, ALL (Strehl et al, 2006;Gulten et al, 2009;Saito et al, 2010) (Santos et al, 2010a,b) (Osaka et al, 1999;Yamamoto et al, 2002;Strehl et al, 2006;Kreuziger et al, 2007) Hypermethylation Colon and head and neck (He et al, 2010;Tierling et al, 2010;Quyun et al, 2010) (Grutzmann et al, 2008;deVos et al, 2009) (Bennett et al, 2008;Lofton-Day et al, 2008;Stanbery et al, 2010) Deletion Ovary, breast Russell et al, 2000) Hodgkin lymphoma (Giefing et al, 2008) SEPT10 None None SEPT11 Gene fusion Deletion AML (Santos et al, 2010b;Stevens et al, 2010) Deletion Liver SEPT12 None None SEPT13 None None SEPT14 None None (Montagna et al, 2003) and the Russell group established that SEPT9 overexpression occurs in various human tumors (Scott et al, 2005). The discovery of DNA hypermethylation at the promoter region of SEPT9 in colorectal (deVos et al, 2009) and head and neck cancer patients (Bennett et al, 2008) complicated the conflicti...…”

“…This member of the septin family is characterized by a large number of isoform splice variants including both amino and carboxyl variants (McIlhatton et al, 2001). The fusion proteins that have been reported so far (summarized in Table 3) result in the loss of exons one and two (Kreuziger et al, 2007). The outcome of these rearrangements is the loss of the variable region at the N-terminus of the protein that characterizes SEPT9 isoforms _v1 and _v2.…”

MLL-SEPTIN gene fusions in hematological malignancies

“…The MLL-SEPT9 fusion, resulting from a translocation between 11q23 and 17q25, has been described to date in 12 cases (Table 1, Figure 1) (Osaka et al, 1999;Taki et al, 1999;Yamamoto et al, 2002;Shih et al, 2006;Kreuziger et al, 2007;Kurosu et al, 2008;Saito et al, 2010;Santos et al, 2010b). As opposed to other cases with MLL-SEPTIN fusions, MLL-SEPT9 patients are very heterogeneous regarding both age (4 months-72 years) and clinical presentation: one MDS case, two t-AML cases and nine cases of de novo AML.…”

A pooled analysis of the diagnostic efficacy of plasmic methylated septin-9 as a novel biomarker for colorectal cancer

“…Among the methylated genes in CRC, septin-9 has been highlighted as an ideal candidate biomarker (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Septin-9 was initially identified in myeloid neoplasia (20). It acts as a suppressor gene in numerous cancer types (21,22).…”