Therapy-related myelodysplastic syndrome and acute myeloid leukemia 
(t-MDS/t-AML) are late complications of cytotoxic therapy used in the treatment 
of malignant diseases. The most common subtype of t-AML ( approximately 75% of 
cases) develops after exposure to alkylating agents, and is characterized by 
loss or deletion of chromosome 5 and/or 7 [-5/del(5q), -7/del(7q)], and a poor 
outcome (median survival 8 months). In the University of Chicago's series of 386 
patients with t-MDS/t-AML, 79 (20%) patients had abnormalities of chromosome 5, 
95 (25%) patients had abnormalities of chromosome 7, and 85 (22%) patients had 
abnormalities of both chromosomes 5 and 7. t-MDS/t-AML with a -5/del(5q) is 
associated with a complex karyotype, characterized by trisomy 8, as well as loss 
of 12p, 13q, 16q22, 17p (TP53 locus), chromosome 18, and 20q. In addition, this 
subtype of t-AML is characterized by a unique expression profile (higher 
expression of genes) involved in cell cycle control (CCNA2, CCNE2, CDC2), 
checkpoints (BUB1), or growth (MYC), loss of expression of IRF8, and 
overexpression of FHL2. Haploinsufficiency of the RPS14, EGR1, APC, NPM1, and 
CTNNA1 genes on 5q has been implicated in the pathogenesis of MDS/AML. In 
previous studies, we determined that Egr1 acts by haploinsufficiency and 
cooperates with mutations induced by alkylating agents to induce myeloid 
leukemias in the mouse. To identify mutations that cooperate with Egr1 
haploinsufficiency, we used retroviral insertional mutagenesis. To date, we have 
identified two common integration sites involving genes encoding transcription 
factors that play a critical role in hematopoiesis (Evi1 and Gfi1b loci). Of 
note is that the EVI1 transcription factor gene is deregulated in human AMLs, 
particularly those with -7, and abnormalities of 3q. Identifying the genetic 
pathways leading to t-AML will provide new insights into the underlying biology 
of this disease, and may facilitate the identification of new therapeutic 
targets.