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1.
Cancer Genet ; 278-279: 80-83, 2023 11.
Article in English | MEDLINE | ID: mdl-37742392

ABSTRACT

The dramatic improvement in the event-free survival of paediatric B-lymphoblastic leukaemia (B-ALL) has led to risk-stratified treatment. Through a combination of clinical features, cytogenetic abnormalities and assessment of treatment response, patients are stratified to receive different intensities of therapy. The presence of high hyperdiploidy (>50 chromosomes) is considered a favourable genetic feature. Conversely, KMT2A fusion genes in B-ALL are associated with a poor prognosis, resulting in intensification of treatment. We present a seven-year-old female with B-ALL, a high hyperdiploid karyotype (56 chromosomes) and KMT2A rearrangement detected on FISH, but with no productive fusion identified. Single nucleotide polymorphism (SNP) array suggested the KMT2A rearrangement was due to chromosome 11 chromothripsis. Subsequent targeted RNA fusion panel and whole transcriptomic sequencing (mRNA-seq) did not detect an expressed KMT2A fusion. Differential expression analyses of the mRNA-seq data led to clustering of this case with other hyperdiploid cases, consistent with the hyperdiploid cytogenetic results. Given the additional intensity and potential toxicity of high-risk treatment, unusual findings by chromosome analysis, FISH and/or chromosomal microarray should prompt consideration of testing for a KMT2A fusion by another method to avoid misclassification.


Subject(s)
Lymphoma, Non-Hodgkin , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Female , Humans , In Situ Hybridization, Fluorescence , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Chromosome Aberrations , Karyotyping , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , RNA, Messenger
2.
Cell Stem Cell ; 15(6): 775-90, 2014 Dec 04.
Article in English | MEDLINE | ID: mdl-25479751

ABSTRACT

Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer maintained by rare populations of leukemia stem cells (LSCs). Selective targeting of LSCs is a promising approach for treating AML and preventing relapse following chemotherapy, and developing such therapeutic modalities is a key priority. Here, we show that targeting telomerase activity eradicates AML LSCs. Genetic deletion of the telomerase subunit Terc in a retroviral mouse AML model induces cell-cycle arrest and apoptosis of LSCs, and depletion of telomerase-deficient LSCs is partially rescued by p53 knockdown. Murine Terc(-/-) LSCs express a specific gene expression signature that can be identified in human AML patient cohorts and is positively correlated with patient survival following chemotherapy. In xenografts of primary human AML, genetic or pharmacological inhibition of telomerase targets LSCs, impairs leukemia progression, and delays relapse following chemotherapy. Altogether, these results establish telomerase inhibition as an effective strategy for eliminating AML LSCs.


Subject(s)
Indoles/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Neoplastic Stem Cells/drug effects , Niacinamide/analogs & derivatives , Telomerase/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Apoptosis/drug effects , Apoptosis/genetics , Cell Cycle Checkpoints/drug effects , Cell Cycle Checkpoints/genetics , Cells, Cultured , Disease Models, Animal , Gene Expression Regulation, Neoplastic/genetics , Gene Knockout Techniques , Humans , Leukemia, Myeloid, Acute/pathology , Mice , Mice, Inbred C57BL , Neoplastic Stem Cells/physiology , Neoplastic Stem Cells/transplantation , Niacinamide/administration & dosage , Oligonucleotides , RNA, Small Interfering/genetics , Recurrence , Telomerase/genetics , Tumor Suppressor Protein p53/genetics , Xenograft Model Antitumor Assays
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