title: Detection of leukemia-associated MLL-GAS7 translocation early during chemotherapy with DNA topoisomerase II inhibitors.
abstract: Leukemias with MLL gene translocations are a complication of primary cancer treatment with DNA topoisomerase II inhibitors. How early translocations appear during primary cancer treatment has not been investigated. We tracked the leukemic clone with an MLL gene translocation during neuroblastoma therapy in a child who developed acute myeloid leukemia. The karyotype of the leukemic clone showed del(11)(q23). We used panhandle PCR-based methods to isolate the breakpoint junction involving MLL and an unknown partner gene. Marrow DNA from neuroblastoma diagnosis and DNA and RNA from serial preleukemic marrows were examined for the translocation. The karyotypic del(11)(q23) was a cryptic t(11;17). GAS7, a growth arrest-specific gene at chromosome band 17p13, was the partner gene of MLL. Two different MLL-GAS7 fusion transcripts were expressed. The translocation was already detectable by 1.5 months after the start of neuroblastoma treatment. The translocation was not detectable in the marrow at neuroblastoma diagnosis or in peripheral blood lymphocyte DNAs of six normal subjects. GAS7 is a new partner gene of MLL in treatment-related acute myeloid leukemia. MLL gene translocations can be present early during anticancer treatment at low cumulative doses of DNA topoisomerase II inhibitors. Although MLL has many partner genes and most have not been characterized, panhandle PCR strategies afford new means for detecting MLL gene translocations early during therapy when the partner gene is unknown.
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Megonigal
authors.forename: N K
authors.initials: NK
authors.lastname: Cheung
authors.forename: E F
authors.initials: EF
authors.lastname: Rappaport
authors.forename: P C
authors.initials: PC
authors.lastname: Nowell
authors.forename: R B
authors.initials: RB
authors.lastname: Wilson
authors.forename: D H
authors.initials: DH
authors.lastname: Jones
authors.forename: K
authors.initials: K
authors.lastname: Addya
authors.forename: D G
authors.initials: DG
authors.lastname: Leonard
authors.forename: B H
authors.initials: BH
authors.lastname: Kushner
authors.forename: T M
authors.initials: TM
authors.lastname: Williams
authors.forename: B J
authors.initials: BJ
authors.lastname: Lange
authors.forename: C A
authors.initials: CA
authors.lastname: Felix
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D001483:Base Sequence; D015139:Blotting, Southern; D002880:Chromosomes, Human, Pair 11; D002945:Cisplatin / Q000009:adverse effects; D003520:Cyclophosphamide / Q000009:adverse effects; D004268:DNA-Binding Proteins / Q000235:genetics*; D004317:Doxorubicin / Q000009:adverse effects; D005047:Etoposide / Q000009:adverse effects; D005091:Exons; D017809:Fatal Outcome; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007951:Leukemia, Myeloid / Q000139:chemically induced / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011519:Proto-Oncogenes; D013997:Time Factors; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D014178:Translocation, Genetic; D014750:Vincristine / Q000009:adverse effects
chemical_list: D004268:DNA-Binding Proteins; C114909:GAS7 protein, human; C497422:KMT2A protein, human; D009419:Nerve Tissue Proteins; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D011495:Histone-Lysine N-Methyltransferase; D002945:Cisplatin