GSE135866
Cytotoxic therapy-induced effects on both hematopoietic and marrow stromal cells promotes therapy-related myeloid neoplasms
Therapy-related myeloid neoplasms (t-MNs) comprise therapy-related acute myeloid leukemia (t-AML)  and myelodysplastic syndrome (t-MDS), and are a late complication of cytotoxic therapy — chemotherapy and/or radiation therapy — used in the treatment of both malignant and non-malignant diseases. The genetic profile of t-MN is markedly skewed towards high-risk cytogenetic and molecular abnormalities, and complex karyotypes with a del(5q), and TP53 mutation/loss are profoundly over-represented in t-MN as compared with de novo counterparts. To model this genetic subset, we showed that concurrent haploinsufficient expression of the del(5q) tumor suppressor genes, early growth response 1 (EGR1) and adenomatous polyposis coli (APC), cooperate with TP53 (p53) loss to induce myeloid leukemia in mice. The frequency of disease increased upon exposure to the alkylating agent, N-ethyl-N-nitrosurea (ENU) .  In the context of alkylating agent therapy, cell intrinsic loss of the  Egr1 and Apc del(5q) genes was sufficient to promote the development of MDS, but concurrent loss of Trp53 (p53) was required to drive AML development.  We examined RNA expression in 1) LSK (Lin-, Sca1+, Kit+) hematopoietic stem and progenitor cells isolated from mice with Trp53 knockdown or without, prior to myeloid disease development, 2)  bone marrow cells isolated from mice with MDS (no Trp53 knockdown) or AML (Trp53 knockdown), and 3) early passage mesenchymal stromal cells isolated from mice injected i.p. with  10% ethanol (mock) or ENU (100 mg/kg). Overall design: RNA was isolated from LSK (Lin-, Sca1+, Kit+) bone marrow cells prior to myeloid disease development; from total bone marrow of mice that had developed MDS (Egr1, Apc haploinsufficiency without Trp53 knockdown) or AML (Egr1, Apc haploinsufficiency with Trp53 knockdown); and from early passage mesenchymal stromal cells isolated from mice injected i.p. with  10% ethanol (mock) or ENU (100 mg/kg).