title: Both SEPT2 and MLL are down-regulated in MLL-SEPT2 therapy-related myeloid neoplasia.
abstract: BACKGROUND
  A relevant role of septins in leukemogenesis has been uncovered by their involvement as fusion partners in MLL-related leukemia. Recently, we have established the MLL-SEPT2 gene fusion as the molecular abnormality subjacent to the translocation t(2;11)(q37;q23) in therapy-related acute myeloid leukemia. In this work we quantified MLL and SEPT2 gene expression in 58 acute myeloid leukemia patients selected to represent the major AML genetic subgroups, as well as in all three cases of MLL-SEPT2-associated myeloid neoplasms so far described in the literature.
  
  
  METHODS
  Cytogenetics, fluorescence in situ hybridization (FISH) and molecular studies (RT-PCR, qRT-PCR and qMSP) were used to characterize 58 acute myeloid leukemia patients (AML) at diagnosis selected to represent the major AML genetic subgroups: CBFB-MYH11 (n = 13), PML-RARA (n = 12); RUNX1-RUNX1T1 (n = 12), normal karyotype (n = 11), and MLL gene fusions other than MLL-SEPT2 (n = 10). We also studied all three MLL-SEPT2 myeloid neoplasia cases reported in the literature, namely two AML patients and a t-MDS patient.
  
  
  RESULTS
  When compared with normal controls, we found a 12.8-fold reduction of wild-type SEPT2 and MLL-SEPT2 combined expression in cases with the MLL-SEPT2 gene fusion (p = 0.007), which is accompanied by a 12.4-fold down-regulation of wild-type MLL and MLL-SEPT2 combined expression (p = 0.028). The down-regulation of SEPT2 in MLL-SEPT2 myeloid neoplasias was statistically significant when compared with all other leukemia genetic subgroups (including those with other MLL gene fusions). In addition, MLL expression was also down-regulated in the group of MLL fusions other than MLL-SEPT2, when compared with the normal control group (p = 0.023)
  
  
  CONCLUSIONS
  We found a significant down-regulation of both SEPT2 and MLL in MLL-SEPT2 myeloid neoplasias. In addition, we also found that MLL is under-expressed in AML patients with MLL fusions other than MLL-SEPT2.
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal. nscerveira@gmail.com
authors.forename: Nuno
authors.initials: N
authors.lastname: Cerveira
authors.forename: Joana
authors.initials: J
authors.lastname: Santos
authors.forename: Susana
authors.initials: S
authors.lastname: Bizarro
authors.forename: Vera
authors.initials: V
authors.lastname: Costa
authors.forename: Franclim R
authors.initials: FR
authors.lastname: Ribeiro
authors.forename: Susana
authors.initials: S
authors.lastname: Lisboa
authors.forename: Cecília
authors.initials: C
authors.lastname: Correia
authors.forename: Lurdes
authors.initials: L
authors.lastname: Torres
authors.forename: Joana
authors.initials: J
authors.lastname: Vieira
authors.forename: Simone
authors.initials: S
authors.lastname: Snijder
authors.forename: José M
authors.initials: JM
authors.lastname: Mariz
authors.forename: Lucília
authors.initials: L
authors.lastname: Norton
authors.forename: Clemens H
authors.initials: CH
authors.lastname: Mellink
authors.forename: Arjan
authors.initials: A
authors.lastname: Buijs
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
mesh_terms: D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism
chemical_list: C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D010744:Phosphoric Monoester Hydrolases