Fusion ofMLL andMSF in Adult De Novo Acute Myelomonocytic Leukemia (M4) with T(11;17)(Q23;Q25)

Abstract

The MLL gene at chromosome band 11q23 is frequently rearranged and fused to partner genes in acute leukemias. Previously, the MSF gene, also called AF17q25, has been cloned as a fusion partner of the MLL gene in therapy-related or infant acute myelogenous leukemias with t(11;17)(q23;q25). MSF belongs to the septin family of proteins, which includes other MLL fusion partners, hCDCrel1 and Septin 6, and has also been implicated in the pathogenesis of human ovarian tumor and murine T-cell lymphoma. We describe here a 64-year-old man with de novo acute myelomonocytic leukemia (French-American-British subtype M4) with t(11;17)(q23;q25). His leukemia was successfully induced into a first remission, which, however, lasted only briefly. A second remission was never attained, and the patient died of sepsis 16 months after the diagnosis of leukemia. Examination of his leukemic cells at diagnosis revealed an MLL gene rearrangement, by Southern blotting, and an MLL-MSF fusion transcript, by the reverse transcriptase polymerase chain reaction (RT-PCR) method. Sequence analysis of the RT-PCR product further revealed that MLL exon 5 was fused in-frame to MSF exon 3. Further clinical and molecular analyses of acute leukemias with the MLL-MSF transcript may shed more light on the clinical characteristics and molecular mechanisms of the MLL-septin type leukemias.

Hematopoietic gene expression profile in zebrafish kidney marrow

“…It is worth noting that some genes involved in human hematopoietic diseases were uncovered in the present work. For example, the human CRKL gene has been implicated as a substrate for the BCR-ABL tyrosine kinase in chronic myelogenous leukemia (14), and six leukemia-associated genes, MSF, SEPT6, FNBP1, GAS7, ARHGEF12 and ELL, have been identified as components of MLL fusion proteins in leukemia with 11q23 chromosomal translocation (15)(16)(17)(18)(19)(20).…”

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...…”

“…Exon 2 (Yamamoto et al, 2002) Exon 5 Exon 3 (Osaka et al, 1999) Exon 8 Exon 3 It is clear that the mechanisms by which septin genes operate to promote or inhibit tumorigenesis cannot be oversimplified. Tumors that originate in different tissues might be affected by septin deregulation at various levels; alternatively, gene members of the septin family could simply interact with different partners and have various functions in different cell types.…”

The pathobiology of the septin gene family

“…Several human septin genes (SEPT5 [134,135], SEPT6 [136][137][138][139][140], SEPT9 [141][142][143] and SEPT11 [144]; see Table 1) have been observed in reciprocal translocations with MLL on chromosome 11 in patients with leukaemia. While MLL is a remarkably promiscuous leukaemia-associated gene, having more than 50 known partners [145], there are some features that suggest that involvement of septins is not a chance event.…”