Biology subjects

Michael Andreeff

Publications and source records attributed to Michael Andreeff.

2 recordsLinked to original sources

bioRxiv2020

Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype in AML cells through TGF-β-p38-ALDH2 pathway

Mesenchymal stromal cells (MSCs) in the bone marrow (BM) microenvironment have been shown to induce chemotherapy resistance in acute myeloid leukemia (AML) cells, but the mechanism is not clear. We hypothesized that stromal cells induce a stem-like phenotype in AML cells, thereby promoting tumorigenicity and chemotherapy resistance. We found that aldehyde dehydrogenase (ALDH), an enzyme that is highly expressed in hematopoietic as well as leukemic stem cells was dramatically activated in AML cells co-cultured with BM-MSCs mainly through upregulation of a specific isoform, ALDH2. Mechanistic studies revealed that stroma-derived TGF-{beta}1 induced an ALDH+ phenotype in AML cells via the non-canonical TGF-{beta} pathway through p38 activation. Inhibition of ALDH2 using specific inhibitors significantly inhibited BM-MSC-induced ALDH activity and sensitized AML cells to chemotherapy. Collectively, our data indicate that BM stroma induces a stem-like phenotype in AML cells through the non-canonical TGF-{beta} pathway. Inhibition of ALDH2 sensitizes AML cells to chemotherapy. Impact StatementCurrently there is no standard therapy for AML. In this study we identified the mechanism of chemotherapy resistance in AML cells and discovered TGF-{beta}-p38-ALDH2 signaling pathway as a therapeutic target.

cancer biology↗

bioRxiv2020

Evolutionary Action Score of TP53 Mutations: Integrated Clinico-pathologic And Protein Structural Analysis in Myelodysplastic Syndromes

ABSTRACTTo determine the impact of TP53 mutations on the phenotype and outcome of myelodysplastic syndromes, we quantified the deleterious effects of missense TP53 mutations using the computationally-derived evolutionary action score (higher score indicates worse impact), based on the phylogenetic divergence of the sequence position and amino acid change perturbation, and correlated with clinico-pathologic-genomic features in 270 newly-diagnosed TP53-mutant patients primarily treated with hypomethylating agents. Using recursive partitioning and regression trees, we identified a subset of patients with low-EAp53 mutations (≤52) with improved overall survival (OS) (n=17, 6%) compared to high-EAp53 (n=253, 94%) [median OS, 48 vs. 10 months; p=0.01]. Compared to high-EAp53, low-EAp53 patients had lower cytogenetic complexity, lower TP53 protein expression, lacked multi-allelic TP53 alterations, but had more somatic mutations in other genes. There was no difference in median TP53 variant allele frequency or distribution of R-IPSS. 3D-protein modeling showed clustering of poor-outcome mutations, indicating structural location influences outcome.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗