Cytotoxic Therapy-Induced Effects on Both Hematopoietic and Marrow Stromal Cells Promotes Therapy-Related Myeloid Neoplasms. 2020

Angela Stoddart, and Jianghong Wang, and Anthony A Fernald, and Elizabeth M Davis, and Camille R Johnson, and Chunmei Hu, and Jason X Cheng, and Megan E McNerney, and Michelle M Le Beau
Department of Medicine, The University of Chicago, Chicago, Illinois. astoddar@bsd.uchicago.edu.

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.

UI MeSH Term Description Entries
D007951 Leukemia, Myeloid Form of leukemia characterized by an uncontrolled proliferation of the myeloid lineage and their precursors (MYELOID PROGENITOR CELLS) in the bone marrow and other sites. Granulocytic Leukemia,Leukemia, Granulocytic,Leukemia, Myelocytic,Leukemia, Myelogenous,Myelocytic Leukemia,Myelogenous Leukemia,Myeloid Leukemia,Leukemia, Monocytic, Chronic,Monocytic Leukemia, Chronic,Chronic Monocytic Leukemia,Chronic Monocytic Leukemias,Granulocytic Leukemias,Leukemia, Chronic Monocytic,Leukemias, Chronic Monocytic,Leukemias, Granulocytic,Leukemias, Myelocytic,Leukemias, Myelogenous,Leukemias, Myeloid,Monocytic Leukemias, Chronic,Myelocytic Leukemias,Myelogenous Leukemias,Myeloid Leukemias
D001853 Bone Marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Marrow,Red Marrow,Yellow Marrow,Marrow, Bone,Marrow, Red,Marrow, Yellow
D002872 Chromosome Deletion Actual loss of portion of a chromosome. Monosomy, Partial,Partial Monosomy,Deletion, Chromosome,Deletions, Chromosome,Monosomies, Partial,Partial Monosomies
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D016158 Genes, p53 Tumor suppressor genes located on the short arm of human chromosome 17 and coding for the phosphoprotein p53. Genes, TP53,TP53 Genes,p53 Genes,Gene, TP53,Gene, p53,TP53 Gene,p53 Gene
D016609 Neoplasms, Second Primary Abnormal growths of tissue that follow a previous neoplasm but are not metastases of the latter. The second neoplasm may have the same or different histological type and can occur in the same or different organs as the previous neoplasm but in all cases arises from an independent oncogenic event. The development of the second neoplasm may or may not be related to the treatment for the previous neoplasm since genetic risk or predisposing factors may actually be the cause. Neoplasms, Metachronous,Neoplasms, Metachronous Second Primary,Neoplasms, Therapy-Related,Neoplasms, Treatment-Related,Second Malignancy,Second Neoplasm,Second Primary Neoplasms,Therapy-Associated Neoplasms,Therapy-Related Cancer,Treatment-Associated Neoplasms,Treatment-Related Cancer,Cancer, Second Primary,Metachronous Neoplasms,Metachronous Second Primary Neoplasms,Neoplasms, Therapy-Associated,Neoplasms, Treatment-Associated,Second Cancer,Second Primary Neoplasms, Metachronous,Therapy-Associated Cancer,Therapy-Related Neoplasms,Treatment-Associated Cancer,Treatment-Related Neoplasms,Cancer, Second,Cancer, Therapy-Associated,Cancer, Therapy-Related,Cancer, Treatment-Associated,Cancer, Treatment-Related,Cancers, Second,Cancers, Second Primary,Cancers, Therapy-Associated,Cancers, Therapy-Related,Cancers, Treatment-Associated,Cancers, Treatment-Related,Malignancies, Second,Malignancy, Second,Metachronous Neoplasm,Neoplasm, Metachronous,Neoplasm, Second,Neoplasm, Second Primary,Neoplasm, Therapy-Associated,Neoplasm, Therapy-Related,Neoplasm, Treatment-Associated,Neoplasm, Treatment-Related,Neoplasms, Second,Neoplasms, Therapy Associated,Neoplasms, Therapy Related,Neoplasms, Treatment Associated,Neoplasms, Treatment Related,Second Cancers,Second Malignancies,Second Neoplasms,Second Primary Cancer,Second Primary Cancers,Second Primary Neoplasm,Therapy Associated Cancer,Therapy Associated Neoplasms,Therapy Related Cancer,Therapy Related Neoplasms,Therapy-Associated Cancers,Therapy-Associated Neoplasm,Therapy-Related Cancers,Therapy-Related Neoplasm,Treatment Associated Cancer,Treatment Associated Neoplasms,Treatment Related Cancer,Treatment Related Neoplasms,Treatment-Associated Cancers,Treatment-Associated Neoplasm,Treatment-Related Cancers,Treatment-Related Neoplasm
D017154 Stromal Cells Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. Cell, Stromal,Cells, Stromal,Stromal Cell
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D059016 Tumor Microenvironment The milieu surrounding neoplasms consisting of cells, vessels, soluble factors, and molecules, that can influence and be influenced by, the neoplasm's growth. Cancer Microenvironment,Cancer Microenvironments,Microenvironment, Cancer,Microenvironment, Tumor,Microenvironments, Cancer,Microenvironments, Tumor,Tumor Microenvironments
D018906 Antineoplastic Agents, Alkylating A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026) Alkylating Agents, Antineoplastic,Alkylating Antineoplastic Agents,Alkylating Antineoplastic Drugs,Alkylating Antineoplastics,Alkylating Drugs, Antineoplastic,Antineoplastic Alkylating Agents,Antineoplastic Drugs, Alkylating,Antineoplastics, Alkylating,Antineoplastic Alkylating Drugs,Drugs, Antineoplastic Alkylating

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