Table 4.

Therapy-related myelodysplastic syndrome and their genetic and clinical pathways.

Pathway	Clinical features	Genetic and biologic features
Alkylating agents inter- and intrastrand DNA crosslinks	Longer latency, median 5–7 years Older patients Preceded by dysplastic phase Deletion or loss of 5q and/or 7q or complete loss of chromosome 5 and 7 Poor response to standard induction chemotherapy	Alkylating agents have reactive groups that interact covalently with nucleophilic sites in DNA Diadduct/Monoadduct ratio proportional to leukemogenicity Melphalan induces nonrandom chromosome breaks, e.g., chromosomes 5,7, 11, and 17. Clustering of break points at centromeric or pericentric region of several chromosomes, including chromosome 5 and 7.
Topoisomerase II inhibitors intercalate dsDNA	Short latency, median 1–3 years Younger patients No dysplastic phase Balanced chromosome aberrations, e.g., MLL 11q23, RUNX1/AML1 21q22, PML-RARA t(15;17) More favorable response to standard induction chemotherapy	Antitumor antibiotics and epipodophyllotoxins Intercalate dsDNA → stabilize DNA-topoisomerase complex which collides with the replication fork or transcriptional machinery → double strand breaks Double strand breaks occur frequently at loci of hematopoietic transcription factors e.g., MLL, AML1, CBFB, RARA, NUP98 Double strand breaks colocalize with DNaseI hypersensitivity sites that have open chromatin structure

Alkylating agents, examples include: melphalan, cyclophosphamide, busulfan, carmustine, cisplatin, carboplatin, dacarbazine, chlorambucil

Antitumor antibiotics and epipodophyllotoxins, examples include: etoposide, doxorubicin, daunorubicin, mitoxantrone