Clonal Competition Assays Identify Fitness Signatures in Cancer Progression and Resistance in Multiple Myeloma
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ABSTRACT:
PROVIDER: PRJNA1036646 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26709301.fastq.gz | Fastqsanger.gz | |||
| SRR26709302.fastq.gz | Fastqsanger.gz | |||
| SRR26709303.fastq.gz | Fastqsanger.gz | |||
| SRR26709304.fastq.gz | Fastqsanger.gz | |||
| SRR26709305.fastq.gz | Fastqsanger.gz |
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Project description:This SuperSeries is composed of the following subset Series: GSE36822: Clonal competition with alternating dominance in multiple myeloma [244kCGH] GSE36823: Clonal competition with alternating dominance in multiple myeloma [44kCGH] GSE36824: Clonal competition with alternating dominance in multiple myeloma [GEP] Refer to individual Series
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Project description:Multiple Myeloma is a genetically heterogeneous disease and the management of relapses is one of the biggest clinical challenges. TP53 alterations are established high-risk markers of MM and are included in the current disease staging criteria. KRAS is the most frequently mutated gene affecting around 20% of MM patients. Applying Clonal Competition Assays (CCA) co-culturing color-labeled genetically modified cell lines, we recently showed that both, mono- and biallelic single-point mutations in TP53 transmit a fitness advantage to the cells. Here we report a similar dynamic for two mutations in KRAS (G12A and A146T). The fitness benefit of TP53 and KRAS mutations was treatment-independent, unlike patient-derived drug resistance alterations that only induce an advantage when the drug is present. CUL4B KO and IKZF1 A152T, both previously confirmed to transmit resistance against immunomodulatory agents, as well as PSMB5 A20T, a mutation located in the binding site of proteasome inhibitors do not transfer a fitness advantage to the cells per se, rather a disadvantage in comparison to the wildtype cell line. They only outcompete the culture when the respective drug was applied. Thus, to prevent the selection of clones harboring the potential of inducing a relapse, these results argue in favor of treatment-free breaks or alternatively for a switch of the drug class given as maintenance therapy. Furthermore, our data gives a biological rationale for the high frequency of KRAS and TP53 alterations at MM relapse. CCAs are suitable models for the study of clonal evolution and competitive (dis)advantages conveyed by a specific genetic lesion of interest, in dependence on external factors such as the treatment.
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Project description:All cancers emerge following a period of clonal selection and subsequent clonal expansion. Whilst the evolutionary principles imparted by genetic intra-tumour heterogeneity (ITH) are becoming increasingly clear, little is known about the non-genetic mechanisms that contribute to ITH and malignant clonal fitness. Using SPLINTR, a synthetic expressed barcoding strategy, in three clinically relevant mouse models of acute myeloid leukaemia (AML) we find that malignant clonal dominance is a stable and heritable property that is facilitated by the repression of antigen presentation and the increased expression of Slpi, a leukocyte protease inhibitor that has not previously been characterised in AML. Increased transcriptional heterogeneity is a consistent feature enabling clonal fitness in diverse tissue / immune microenvironments and in the context of clonal competition between genetically distinct clones within a uniform microenvironment. Compared to extramedullary sites, leukaemia initiating capacity is most enriched in malignant cells resident within the bone marrow microenvironment and leukaemia stem cells (LSC), like normal haematopoietic stem cells, display heritable clone-intrinsic properties of high, and low clonal output that contribute to the overall tumour mass. Finally, we demonstrate that clonal output does not dictate sensitivity to chemotherapy and both high and low output LSC clones retain marked cellular plasticity enabling them to survive potent therapeutic challenge and persist as minimal residual disease. Together these data provide fundamental insights into the non-genetic transcriptional processes that underpin malignant clonal fitness which may inform future therapeutic strategies.
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Project description:All cancers emerge following a period of clonal selection and subsequent clonal expansion. Whilst the evolutionary principles imparted by genetic intra-tumour heterogeneity (ITH) are becoming increasingly clear, little is known about the non-genetic mechanisms that contribute to ITH and malignant clonal fitness. Using SPLINTR, a synthetic expressed barcoding strategy, in three clinically relevant mouse models of acute myeloid leukaemia (AML) we find that malignant clonal dominance is a stable and heritable property that is facilitated by the repression of antigen presentation and the increased expression of Slpi, a leukocyte protease inhibitor that has not previously been characterised in AML. Increased transcriptional heterogeneity is a consistent feature enabling clonal fitness in diverse tissue / immune microenvironments and in the context of clonal competition between genetically distinct clones within a uniform microenvironment. Compared to extramedullary sites, leukaemia initiating capacity is most enriched in malignant cells resident within the bone marrow microenvironment and leukaemia stem cells (LSC), like normal haematopoietic stem cells, display heritable clone-intrinsic properties of high, and low clonal output that contribute to the overall tumour mass. Finally, we demonstrate that clonal output does not dictate sensitivity to chemotherapy and both high and low output LSC clones retain marked cellular plasticity enabling them to survive potent therapeutic challenge and persist as minimal residual disease. Together these data provide fundamental insights into the non-genetic transcriptional processes that underpin malignant clonal fitness which may inform future therapeutic strategies.
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Project description:Identifying non-genetic determinants of malignant clonal fitness at single cell resolution (clonal competition scRNAseq)
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Project description:Copy number and Gene expression profiling multiple myeloma patients at multiple stages of their individual clinical course Identification of evolutionary paterns in multiple myeloma Copy number differences between individual CD138 purified tumor populations from multiple myeloma patients and control female using the Agilent 244A Human CGH microarray
2012-03-27 | E-GEOD-36822 | biostudies-arrayexpress
Project description:Copy number and Gene expression profiling multiple myeloma patients at multiple stages of their individual clinical course Identification of evolutionary paterns in multiple myeloma Copy number differences between individual CD138 purified tumor populations from multiple myeloma patients and control female using the Agilent 44B Human CGH microarray
2012-03-27 | E-GEOD-36823 | biostudies-arrayexpress
Project description:All cancers emerge following a period of clonal selection and subsequent clonal expansion. Whilst the evolutionary principles imparted by genetic intra-tumour heterogeneity (ITH) are becoming increasingly clear, little is known about the non-genetic mechanisms that contribute to ITH and malignant clonal fitness. Using SPLINTR, a synthetic expressed barcoding strategy, in three clinically relevant mouse models of acute myeloid leukemia (AML) we find that malignant clonal dominance is a stable and heritable property that is facilitated by the repression of antigen presentation and the increased expression of Slpi, a leukocyte protease inhibitor that has not previously been characterised in AML. Increased transcriptional heterogeneity is a consistent feature enabling clonal fitness in diverse tissue / immune microenvironments and in the context of clonal competition between genetically distinct clones within a uniform microenvironment. Compared to extramedullary sites, leukemia initiating capacity is most enriched in malignant cells resident within the bone marrow microenvironment and leukemia stem cells (LSC), like normal haematopoietic stem cells, display heritable clone-intrinsic properties of high, and low clonal output that contribute to the overall tumour mass. Finally, we demonstrate that clonal output does not dictate sensitivity to chemotherapy and both high and low output LSC clones retain marked cellular plasticity enabling them to survive potent therapeutic challenge and persist as minimal residual disease. Together these data provide fundamental insights into the non-genetic transcriptional processes that underpin malignant clonal fitness which may inform future therapeutic strategies.
2021-11-08 | GSE186305 | GEO
Project description:All cancers emerge following a period of clonal selection and subsequent clonal expansion. Whilst the evolutionary principles imparted by genetic intra-tumour heterogeneity (ITH) are becoming increasingly clear, little is known about the non-genetic mechanisms that contribute to ITH and malignant clonal fitness. Using SPLINTR, a synthetic expressed barcoding strategy, in three clinically relevant mouse models of acute myeloid leukemia (AML) we find that malignant clonal dominance is a stable and heritable property that is facilitated by the repression of antigen presentation and the increased expression of Slpi, a leukocyte protease inhibitor that has not previously been characterised in AML. Increased transcriptional heterogeneity is a consistent feature enabling clonal fitness in diverse tissue / immune microenvironments and in the context of clonal competition between genetically distinct clones within a uniform microenvironment. Compared to extramedullary sites, leukemia initiating capacity is most enriched in malignant cells resident within the bone marrow microenvironment and leukemia stem cells (LSC), like normal haematopoietic stem cells, display heritable clone-intrinsic properties of high, and low clonal output that contribute to the overall tumour mass. Finally, we demonstrate that clonal output does not dictate sensitivity to chemotherapy and both high and low output LSC clones retain marked cellular plasticity enabling them to survive potent therapeutic challenge and persist as minimal residual disease. Together these data provide fundamental insights into the non-genetic transcriptional processes that underpin malignant clonal fitness which may inform future therapeutic strategies.
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