Novel SH3 protein encoded by the AF3p21 gene is fused to the mixed lineage leukemia protein in a therapy-related leukemia with t(3;11) (p21;q23).
The mixed lineage leukemia (MLL) gene located at chromosome band 11q23 is frequently rearranged in patients with therapy-related acute monocytic leukemia who received topoisomerase II inhibitors. We have identified a novel fusion partner of MLL (FAB M5b) in a patient who developed t-AML 9 years after treatment for acute lymphoblastic leukemia (ALL). The leukemic cells had a sole karyotypic abnormality of t(3;11) (p21;q23). Screening of a genomic DNA library, prepared from leukemic cell DNA, identified rearranged clones composed of MLL and a novel gene on chromosome 3p21 (AF3p21). The AF3p21 gene encodes a protein of 722 amino acids, which contains an Src homology 3 (SH3) domain, a proline-rich domain, and a bipartite nuclear localizing signal (NLS). RNA analysis demonstrated that exon 6 of the MLL gene fused to exon 2 of the AF3p21 gene. The resulting chimeric protein consists of AT-hooks, methyltransferase, and transcription repressor domains of MLL in addition to the AF3p21 proline-rich domain and NLS but not the AF3p21 SH3 domain.
Sano
K
K
Department of Pediatrics, Kobe University School of Medicine, Kobe, Japan. sanoped@kobe-u.ac.jp
Hayakawa
A
A
Piao
J H
JH
Kosaka
Y
Y
Nakamura
H
H
D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000595:Amino Acid Sequence; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D018076:DNA, Complementary / Q000235:genetics; D003630:Daunorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000628:therapy; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy; D008969:Molecular Sequence Data; D009124:Muscle Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000628:therapy; D009607:Nitrosourea Compounds / Q000008:administration & dosage / Q000009:adverse effects; D009687:Nuclear Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D018909:src Homology Domains / Q000235:genetics*
C404148:AF3p21-MLL fusion protein, human; D048868:Adaptor Proteins, Signal Transducing; D018076:DNA, Complementary; D009124:Muscle Proteins; C486062:NCKIPSD protein, human; D009607:Nitrosourea Compounds; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D005047:Etoposide; D003520:Cyclophosphamide; C020766:ranimustine; D003630:Daunorubicin