Cytogenetic and genetic pathways in therapy-related acute myeloid leukemia

Abstract

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.

Figure 1

Cytogenetic abnormalities in patients with t-MDS/t-AML (N=386) in the University of Chicago series. Gain of chromosomal material is depicted by green bars to the right of each chromosome, and loss of chromosomal material is depicted by red bars. Numbers above the bars indicate the number of patients with this abnormality. Arrowheads identify the location of the breakpoints of structural rearrangements, and the numbers next to the arrowheads indicate the number of rearrangements with the corresponding breakpoint.

Figure 2

Idiogram of the long arm of chromosome 5 showing chromosome markers and candidate genes within CDSs as reported by various investigators. The proximal CDS in 5q31.2 was identified in MDS, AML and t-MDS/t-AML, whereas the distal CDS in 5q33.1 was identified in MDS with an isolated del(5q) (the 5q-Syndrome).

Figure 3

Survival curves of WT and Egr1-deficient mice after ENU treatment at (A) 4 wks or (B) 20 wks of age. **Only one WT mouse treated at 20 wks developed a lymphoma; two were sacrificed due to severe dermatitis.

Figure 4

The network of genes regulating myeloid cell fate at the level of the granulocyte-monocyte progenitor, illustrating some, but not all, of the factors that regulate cell fate. Lines ending in arrows indicate positive regulation, and lines ending in bars indicate inhibitory effects. The thickness of the lines indicates the relative strength of the effect. See text for a description of this network. Adapted from reference .

Figure 5

Cooperating genetic mutations leading to t-MDS/t-AML with a del(5q).