Different genetic pathways in leukemogenesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia

Abstract

Development of myelodysplasia (MDS) with subsequent progression to acute myeloid leukemia (AML) is an example of the multistep process of malignant transformation in which each step often relates to genetic abnormalities that can be directly seen as chromosomal aberrations. Therapy-related MDS and AML (t-MDS and t-AML) may serve as an ideal model for a study of the genetic evolution of MDS and AML because chromosomal abnormalities are observed in most cases and because the disease is often diagnosed early due to a close patient follow-up. The cytogenetic characteristics at diagnosis were studied in 137 consecutive cases of t-MDS and t-AML, including 22 new cases, and correlated with the clinical characteristics and the course of the disease. Balanced translocations to chromosome bands 11q23 and 21q22 represent primary steps in pathways leading directly to overt t-AML. Specific chromosomal deletions or losses, on the other hand, represent primary or secondary events in alternative pathways leading to t-MDS with potential for subsequent transformation to overt t-AML. Loss of a whole chromosome 7 (-7) or deletion of its long arm (7q-) and deletion of the long arm of a chromosome 5 (5q-) were the most frequent primary abnormalities significantly related to t-MDS. Loss of a whole chromosome 5 (-5) was also a primary event, but surprisingly, was observed equally in t-MDS and in t-AML. Deletion of chromosome 13, including bands q13q14, was another less common primary aberration of t- MDS. Except for -7 and del(13q), these primary aberrations were most often observed together with secondary abnormalities. These included balanced aberrations involving band 3q26 and various deletions of chromosome 3, a gain of a whole chromosome 8, deletions of the short arm or loss of chromosomes 12 and 17, loss of a whole chromosome 18, and deletions of the short arm of chromosome 21. Deletions or loss or chromosomes 5 and 7 were significantly associated with previous therapy with alkylating agents (P = .002), and balanced translocations to chromosome bands 3q26, 11q23, and 21q22 were significantly associated with previous therapy with drugs targeting DNA-topoisomerase II (P < .00005). Other characteristic aberrations were not related to any specific type of therapy. The molecular changes believed to contribute to the development of t-MDS and t-AML have been identified for many of these chromosomal abnormalities.

Therapy‐related myeloid neoplasms: pathobiology and clinical characteristics

“…In addition to alkylating agents, DNA topoisomerase inhibitors were identified as inducing a distinct form of t-MNs (Pedersen-Bjergaard et al, 1991). While alkylating agents associated with t-MNs are characterized by a complex karyotype often featuring partial or complete loss of chromosomes 5 and/or 7, exposure to topoisomerase inhibitors leads to the development of leukaemias with balanced translocations involving MLL at 11q23, RUNX1 at 21q22 and RARA at 17q21 (Pedersen-Bjergaard et al, 1995;Dissing et al, 1998;Smith et al, 2003). DNA topoisomerases are critical enzymes responsible for unknotting and relaxing supercoiled DNA, thus allowing DNA replication to occur.…”

Therapy-related myelodysplastic syndrome developed by dacarbazine, nimustine hydrochloride and vincristine sulfate (DAV) therapy for patient with malignant melanoma

“…Myelodysplastic syndrome (MDS) was observed in TML after chemotherapy with alkylating agents for first cancer. 2 MDS in de novo is characterized by )5 or 5q-, )7 or 7q-, +8, +19, 20q-and +21 chromosomal changes, while therapy-related myelodysplastic syndrome (t-MDS) related to alkylating agent is characterized by )5, deletion (5), addition (7), and 7q-chromosomal changes, but not by +8, +19 and 20q-. [3][4][5][6] Patients who have deep malignant melanoma (MM) (T4, >4 mm) or regional draining lymph nodes have a high relapse and mortality rate of 50-90%.…”

“…2 MDS in de novo is characterized by )5 or 5q-, )7 or 7q-, +8, +19, 20q-and +21 chromosomal changes, while therapy-related myelodysplastic syndrome (t-MDS) related to alkylating agent is characterized by )5, deletion (5), addition (7), and 7q-chromosomal changes, but not by +8, +19 and 20q-. [3][4][5][6] Patients who have deep malignant melanoma (MM) (T4, >4 mm) or regional draining lymph nodes have a high relapse and mortality rate of 50-90%. 7 Although MM has been refractory to most chemotherapeutic agents, Japanese groups have been given a combination of dacarbazine (80-140 ⁄ m 2 per day on the first to fifth days), nimustine hydrochloride (50-80 ⁄ m 2 per day on the second and fourth days) and vincristine sulfate (0.5-0.8 ⁄ m 2 per day on the first day) (DAV therapy) as a postoperative therapy of MM for a long time.…”

How I investigate Clonal cytogenetic abnormalities of undetermined significance

“…40 Del(5q) is detected in ~ 20% of patients with t-MDS/AML. 41 In an earlier study of 21 patients who acquired isolated del(5q) after cytotoxic therapy, 24 12(57%) patients developed t-MDS or t-AML and 9 patients did not. Interestingly, 4 of 21 patients had deletions that spared both…”