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MLL chimeric protein activation renders cells vulnerable to chromosomal damage: An explanation for the very short latency of infant leukemia
Author(s) -
Eguchi Mariko,
EguchiIshimae Minenori,
Knight Deborah,
Kearney Lyndal,
Slany Robert,
Greaves Mel
Publication year - 2006
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20338
Subject(s) - biology , fusion gene , cancer research , leukemia , phenotype , myeloid leukemia , haematopoiesis , fusion protein , progenitor cell , dna damage , myeloid , gene , genetics , immunology , dna , stem cell , recombinant dna
MLL fusion genes are a predominant feature of acute leukemias in infants and in secondary acute myeloid leukemia (AML) associated with prior chemotherapy with topo‐II poisons. The former is considered to possibly arise in utero via transplacental chemical exposure. A striking feature of these leukemias is their malignancy and remarkably brief latencies implying the rapid acquisition of any necessary additional mutations. We have suggested that these coupled features might be explained if MLL fusion gene encoded proteins rendered cells more vulnerable to further DNA damage and mutation in the presence of chronic exposure to the agent(s) that induced the MLL fusion itself. We have tested this idea by exploiting a hormone regulated MLL‐ENL (MLLT1) activation system and show that MLL‐ENL function in normal murine progenitor cells substantially increases the incidence of chromosomal abnormalities in proliferating cells that survive exposure to etoposide VP‐16. This phenotype is associated with an altered pattern of cell cycle arrest and/or apoptosis. © 2006 Wiley‐Liss, Inc.