Project description:We establish a Cre-ERT2-loxP (causes recombination, estrogen receptor mutant T2, locus of X-over P1) based inducible RNAi- (ribonucleic acid interference) mediated gene silencing system in patient-derived xenograft (PDX) models of acute leukemias in vivo. Mimicking anti-cancer therapy in patients, gene inhibition is initiated in mice harboring orthotopic tumors. In fluorochrome guided, competitive in vivo trials, silencing of DUX4 (double homeobox 4) playes an essential role in patients’ leukemias carrying the recently described DUX4-IGH (immunoglobulin heavy chain) translocation, while the downstream mediator DDIT4L (DNA-damage-inducible transcript 4 like) is identified as therapeutic vulnerability.
Project description:We establish a Cre-ERT2-loxP (causes recombination, estrogen receptor mutant T2, locus of X-over P1) based inducible RNAi- (ribonucleic acid interference) mediated gene silencing system in patient-derived xenograft (PDX) models of acute leukemias in vivo. Mimicking anti-cancer therapy in patients, gene inhibition is initiated in mice harboring orthotopic tumors. In fluorochrome guided, competitive in vivo trials, silencing of the apoptosis regulator MCL1 (myeloid cell leukemia sequence 1) correlates to pharmacological MCL1 inhibition in patients´ tumors, demonstrating the ability of the method to detect therapeutic vulnerabilities.
Project description:We generate CRISPR/Cas9 patient derived xenograft (PDX) models of acute myeloid leukemia. Mimicking anti-cancer therapy in patients, PDX cells with gene knockouts were re-transplanted into mice. In fluorochromes guided, competitive in vivo trials, a subset of PDX models showed a clear growth disadvantage upon knockout, indicating essential functions for WT1 and DNMT3A.
Project description:Mass spectrometry profiling of orthotopically transplanted breast cancer patient-derived xenograft (PDX) tumors prior to chemotherapy treatment.