Cytotoxic therapy-induced effects on both hematopoietic and marrow stromal cells promotes therapy-related myeloid neoplasms
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA560371 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9972610.fastq.gz | Fastqsanger.gz | |||
| SRR9972620.fastq.gz | Fastqsanger.gz | |||
| SRR9972630.fastq.gz | Fastqsanger.gz | |||
| SRR9972640.fastq.gz | Fastqsanger.gz | |||
| SRR9972611.fastq.gz | Fastqsanger.gz |
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Project description:Therapy-related myeloid neoplasms (t-MNs) following treatment with alkylating agents are characterized by a del(5q), complex karyotypes, alterations of TP53, and a dismal prognosis. To decipher the molecular pathway(s) leading to the pathogenesis of del(5q) t-MN and the effect(s) of cytotoxic therapy on the marrow microenvironment, we developed a mouse model with loss of two key del(5q) genes, EGR1 and APC, in hematopoietic cells. We used the well-characterized drug, N-ethyl-N-nitrosurea (ENU) to demonstrate that alkylating agent exposure of stromal cells in the microenvironment increases the incidence of myeloid disease. In addition, loss of Trp53 with Egr1 and Apc was required to drive the development of a transplantable leukemia, and accompanied by the acquisition of somatic mutations in DNA damage response genes. ENU treatment of mesenchymal stromal cells induced cellular senescence, and led to the acquisition of a senescence-associated secretory phenotype, which may be a critical microenvironmental alteration in the pathogenesis of myeloid neoplasms.
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Project description:Loss of chromosome 7 and del(7q) [-7/del(7q)] are recurring cytogenetic abnormalities in hematologic malignancies, including acute myeloid leukemia and therapy-related myeloid neoplasms, and associated with an adverse prognosis. We performed SNP array analysis on de novo and therapy-related myeloid neoplasms and identified a 2.17 Mb commonly deleted segment on chromosome band 7q22.1 containing CUX1, a gene encoding a homeodomain-containing transcription factor. Haploinsufficiency of the highly conserved ortholog, cut, led to hemocyte overgrowth and tumor formation in Drosophila melanogaster. Similarly, haploinsufficiency of CUX1 gave human hematopoietic cells a significant engraftment advantage upon transplantation into immunodeficient mice. These data identify CUX1 as a conserved, haploinsufficient tumor suppressor frequently deleted in myeloid neoplasms. We performed SNP-array analysis of 34 primary patient samples with de novo or therapy-related myeloid leukemia and one acute myeloid leukemia cell line, UoCM1. For patient samples, DNA was obtained from the white blood cells of bone marrow or peripheral blood leukemia specimens. Cytogenetic analysis revealed clonal -7/del(7q) in 17 of the cases.
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