Cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia

Therapy-Related Acute Myeloid Leukemia Following TCHP Chemotherapy in Two HER2+ Breast Cancer Patients

“…The link between t-AML/t-MDS following platinum and taxane-based chemotherapy has been established in patients treated for ovarian cancer [2][3][4]. To our knowledge, there is only one case report that has reported the causal link of TCHP in a patient with breast cancer who subsequently developed t-AML [5]. In patients treated for ovarian cancer, platinum-containing compounds result in an increased risk of t-MDS/t-AML, with carboplatin specifically, resulting in a latency period of approximately four years and more rare AML subtypes [3][4].…”

“…It has been proposed that generalized genomic instability induced by chemotherapy may be a critical factor in the origin of genetic alterations that drive the disease. In a case study of t-AML following treatment for breast cancer, several chromosomal abnormalities were noted, including MYC, KMT2A, TP53 which were impacted by rearrangement, deletion, or amplification that were thought to drive disease progression [5]. The MYC amplification and overexpression promoted increased proliferation, instability, and poor outcome.…”

“…The MYC amplification and overexpression promoted increased proliferation, instability, and poor outcome. Chromosome 11 contained a 11q23.3 rearrangement affecting KMT2A which has previously been linked to leukemogenesis, and there was a loss of function of TP53 on chromosome 17 that also likely contributed to the development of the t-AML [5]. In studies looking at the development of t-AML after any malignancy and chemotherapy regimen, TP53 was reported to be mutated in 20% -50% of patients with t-AML, which is significantly higher than patients with de novo AML.…”

“…Typically, the diagnosis of t-MDS/t-AML is made via a combination of blood counts, bone marrow aspirates, flow cell cytometry, and karyotype analysis [3,5]. The treatment for t-AML is tailored to the patient based upon age, comorbidities, performance status, and cytogenetic features.…”

Current understanding of extrachromosomal circular DNA in cancer pathogenesis and therapeutic resistance

“…DMs are autonomously replicating circular chromatin bodies that lack recognizable centromeres and telomeres and are frequently identified in cytogenetic examinations of metaphase chromosomes in human solid cancer cells [ 102 ]. Unexpectedly, even though DMs are rare in myeloid neoplasms [ 103 ], they are generally associated with myelodysplasia and therapy-related side effects, also resulting in poor prognosis in patients with leukemia [ 104 – 106 ]. Moreover, studies have demonstrated that DMs can evolve toward ring chromosomes that are stabilized by neocentromeres (ectopic centromeres), providing an evolutionary advantage to leukemia cells [ 50 ].…”