Molecular characterization of KMT2A fusion partner genes in 13 cases of pediatric leukemia with complex or cryptic karyotypes.
In pediatric acute leukemias, reciprocal chromosomal translocations frequently cause gene fusions involving the lysine (K)-specific methyltransferase 2A gene (KMT2A, also known as MLL). Specific KMT2A fusion partners are associated with the disease phenotype (lymphoblastic vs. myeloid), and the type of KMT2A rearrangement also has prognostic implications. However, the KMT2A partner gene cannot always be identified by banding karyotyping. We sought to identify such partner genes in 13 cases of childhood leukemia with uninformative karyotypes by combining molecular techniques, including multicolor banding FISH, reverse-transcriptase PCR, and long-distance inverse PCR. Of the KMT2A fusion partner genes, MLLT3 was present in five patients, all with acute lymphoblastic leukemia, MLLT1 in two patients, and MLLT10, MLLT4, MLLT11, and AFF1 in one patient each. Reciprocal reading by long-distance inverse PCR also disclosed KMT2A fusions with PITPNA in one patient, with LOC100132273 in another patient, and with DNA sequences not compatible with any gene in three patients. The most common KMT2A breakpoint region was intron/exon 9 (3/8 patients), followed by intron/exon 11 and 10. Finally, multicolor banding revealed breakpoints in other chromosomes whose biological and prognostic implications remain to be determined. We conclude that the combination of molecular techniques used in this study can efficiently identify KMT2A fusion partners in complex pediatric acute leukemia karyotypes. Copyright © 2016 John Wiley & Sons, Ltd.
Clinical Medicine Postgraduate Program, College of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.|Cytogenetics Department, Bone Marrow Transplantation Unit, National Cancer Institute, Rio de Janeiro, Brazil.
Daniela R
DR
Ney Garcia
Cytogenetics Department, Bone Marrow Transplantation Unit, National Cancer Institute, Rio de Janeiro, Brazil.|Oncology Post Graduation Program, National Cancer Institute, Rio de Janeiro, Brazil.
Mariana T
MT
de Souza
Cytogenetics Department, Bone Marrow Transplantation Unit, National Cancer Institute, Rio de Janeiro, Brazil.|Oncology Post Graduation Program, National Cancer Institute, Rio de Janeiro, Brazil.
Amanda F
AF
de Figueiredo
Institute of Human Genetics, Jena University Hospital, Jena, Germany.
Moneeb A K
MAK
Othman
Institute of Human Genetics, Jena University Hospital, Jena, Germany.
Katharina
K
Rittscher
Oncology Post Graduation Program, National Cancer Institute, Rio de Janeiro, Brazil.
Eliana
E
Abdelhay
Cytogenetics Department, Bone Marrow Transplantation Unit, National Cancer Institute, Rio de Janeiro, Brazil.|Oncology Post Graduation Program, National Cancer Institute, Rio de Janeiro, Brazil.
Roberto R
RR
Capela de Matos
Institute of Pharmaceutical Biology, Diagnostic Center of Acute Leukemia, Goethe-University of Frankfurt, Frankfurt/Main, Germany.
Claus
C
Meyer
Institute of Pharmaceutical Biology, Diagnostic Center of Acute Leukemia, Goethe-University of Frankfurt, Frankfurt/Main, Germany.
Rolf
R
Marschalek
Clinical Medicine Postgraduate Program, College of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.|Martagão Gesteira Institute of Pediatrics and Child Development, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Marcelo G P
MGP
Land
Institute of Human Genetics, Jena University Hospital, Jena, Germany.
Thomas
T
Liehr
Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States.
Raul C
RC
Ribeiro
Clinical Medicine Postgraduate Program, College of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.|Cytogenetics Department, Bone Marrow Transplantation Unit, National Cancer Institute, Rio de Janeiro, Brazil.|Oncology Post Graduation Program, National Cancer Institute, Rio de Janeiro, Brazil.
Maria Luiza Macedo
MLM
Silva
D002648:Child; D002675:Child, Preschool; D003582:Cytogenetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D007223:Infant; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*
C497422:KMT2A protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase
KTM2A; LDI-PCR; MCB-FISH; MLL; childhood acute leukemia; complex karyotypes