title: Molecular emergence of acute myeloid leukemia during treatment for acute lymphoblastic leukemia.
abstract: Therapy-related acute myeloid leukemias (t-AML) with translocations of the MLL gene are associated with the use of topoisomerase II inhibitors. We established the emergence of the malignant clone in a child who developed t-AML with a t(11;19) (q23;p13.3) during treatment for acute lymphoblastic leukemia (ALL). The MLL-ENL and the reciprocal ENL-MLL genomic fusions and their chimeric transcripts were characterized from samples collected at the time of t-AML diagnosis. We used PCR with patient-specific genomic primers to establish the emergence of the MLL-ENL fusion in serially obtained DNA samples. The MLL-ENL fusion was not detectable in bone marrow at the time of ALL diagnosis or after 2 months of chemotherapy (frequency <8.3 x 10(-7) cells(-1)). The genomic fusion was first detected in bone marrow after 6 months of treatment at a frequency of one in 4,000 mononuclear bone marrow cells; the frequency was one in 70 cells after 20 months of therapy. At the first detection of MLL-ENL, the only topoisomerase II inhibitors the patient had received were one dose of daunorubicin and two doses of etoposide. The MLL-ENL fusion was not detectable in blood at the time of ALL diagnosis or after 0.7, 2, 8, 10, and 12 months of therapy but was detectable in blood at 16 months (one in 2.3 x 10(4) cells). Recombinogenic Alu sequences bracketed the breakpoints in both fusions. These data indicate that the malignant clone was not present before therapy, arose early during chemotherapy, and was able to proliferate even during exposure to antileukemic therapy.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Blanco
authors.forename: T
authors.initials: T
authors.lastname: Dervieux
authors.forename: M J
authors.initials: MJ
authors.lastname: Edick
authors.forename: P K
authors.initials: PK
authors.lastname: Mehta
authors.forename: J E
authors.initials: JE
authors.lastname: Rubnitz
authors.forename: S
authors.initials: S
authors.lastname: Shurtleff
authors.forename: S C
authors.initials: SC
authors.lastname: Raimondi
authors.forename: F G
authors.initials: FG
authors.lastname: Behm
authors.forename: C H
authors.initials: CH
authors.lastname: Pui
authors.forename: M V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D001483:Base Sequence; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000235:genetics; D008297:Male; D008957:Models, Genetic; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein; D016609:Neoplasms, Second Primary / Q000209:etiology* / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D059005:Topoisomerase II Inhibitors; D014178:Translocation, Genetic
chemical_list: D017931:DNA Primers; D004273:DNA, Neoplasm; C425207:MLL-ENL oncoprotein, human; D015514:Oncogene Proteins, Fusion; D059005:Topoisomerase II Inhibitors; D051788:Myeloid-Lymphoid Leukemia Protein