Gene expression profiling of CD34+ subsets in Multiple Myeloma and healthy individuals
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Ingmar Bruns
PROVIDER: E-GEOD-24870 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Multiple myeloma (MM) is a clonal plasma cell disorder frequently accompanied by hematopoietic impairment. Genomic profiling of distinct HSPC subsets revealed a consistent deregulation of signaling cascades, including TGF beta signaling, p38MAPK signaling and pathways involved in cytoskeletal organization, migration, adhesion and cell cycle regulation in MM patients.
2010-10-27 | GSE24870 | GEO
Project description:A characteristic of chronic phase CML is accumulation of mature cells in the peripheral blood. It has not been determined if this expansion is explained by the CD34+ cell subset composition. We conducted flowcytometry-based cell sorting to assess the CD34+ subset composition and to retrieve the respective cells. We found a significant increase in the proportion of MEP and a decrease of HSC and GMP in patients with chronic phase CML compared to their healthy counterparts. The absolute number of HSC was similar, whereas CMP, GMP and MEP were expanded 2.8- to 7.7-fold. Gene expression analysis of CD34+ cell subsets showed, that in contrast to the normal developmental hierachy, CML HSC have a transcriptional profile which is similar to CML progenitor subsets and healthy CMP. HSC in healthy individuals show greater distance to their more mature progeny within the developmental hierarchy. As the differences between CML and healthy controls were minor at the progenitor level, we focused on the further characterization of CML HSC. 614 genes were differentially expressed, including downregulation of genes involved in adhesion and migration, regulation of the stem cell pool, and differentiation. We also found abrogation of nuclear receptors NR4A1 and NR4A3, and decreased expression of c-Jun and JunB. Re-expression of c-Jun and JunB in CD34+ cells from CML patients was achieved by co-transfection of NR4A1 and NR4A3. Moreover, we functionally corroborated a decreased adhesion capacity of the CML HSC. Taken together, these findings help to explain the hematological phenotype of CML patients in chronic phase. Experiment Overall Design: CD34+ subsets of 6 patients with chronic phase CML and 5 healthy volunteers were analysed by means of gene expression profiling with the Affymetrix HU-133A 2.0 array
2009-01-13 | E-GEOD-11889 | biostudies-arrayexpress
Project description:Hematopoietic stem cells (HSCs) maintain quiescence by activating specific metabolic pathways, including glycolysis. However, how stress hematopoiesis, including bone marrow transplantation, induces metabolic changes in hematopoietic stem/progenitor cells (HSPCs) remains unclear. Here, we report a critical role for the p38MAPK family isoform p38α in initiating HSPC proliferation during stress hematopoiesis in mouse. We found that p38MAPK is immediately phosphorylated in HSPCs after hematological stress. p38α loss resulted in defective recovery from hematological stress and a delay in initiation of HSPC cycling. Bone marrow transplant altered levels of amino acids and purine-related metabolites in a p38α-dependent manner. Mechanistically, p38α signaling increases expression of inosine-5’-monophosphate dehydrogenase 2 in HSPCs after transplantation, an activity correlated with perturbed cell cycle progression in vitro and in vivo. Overall, we propose a novel mechanism governing HSPC cell cycle initiation via metabolic signaling in response to stress.
2016-04-20 | GSE80420 | GEO
Project description:The MMSET (Multiple Myeloma SET domain) protein is overexpressed in multiple myeloma patients with the translocation t(4;14). Although studies have shown the involvement of MMSET/WHSC1 in development, its mode of action in the pathogenesis of multiple myeloma (MM) is largely unknown. We found that MMSET is a major regulator of chromatin structure and transcription in t(4;14) MM cells. High levels of MMSET correlate with an increase in lysine 36 methylation of histone H3 and a decrease in lysine 27 methylation across the genome, leading to a more open structural state of the chromatin. Loss of MMSET expression alters adhesion properties, suppresses growth and induces apoptosis in MM cells. Consequently, genes affected by high levels of MMSET are implicated in the p53 pathway, cell cycle regulation and integrin signaling. Regulation of many of these genes required functional histone methyl-transferase (HMT) activity of MMSET. These results implicate MMSET as a major epigenetic regulator in t(4;14)+ MM.
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Project description:Bone marrow -adipocytes (BMAs) have recently been implicated in accelerating bone metastatic cancers such as AML and breast cancer. Importantly, bone marrow adipose tissue (BMAT) expands with aging and obesity- two key risk factors in multiple myeloma (MM) disease prevalence- suggesting that BMAs influence and are influenced by myeloma cells in the marrow. Here we examined how myeloma cells affect adipocytes and provide evidence that MM cells alter adipocyte gene expression and cytokine secretion profiles, creating a “MM-associated” adipocyte (MM-adipocyte) phenotype. Our findings indicate that: (1) Multiple myeloma cells decrease BM adiposity in vitro, in myeloma animal models, and in clinical samples, (2) myeloma induces widespread gene expression and phenotypic changes in adipocytes in vitro, most notable, the induction of a senescent-like phenotype in BMAs, (3) MM-adipocytes affect myeloma cell cycle, drug sensitivity, and aggressiveness, illuminating a new driver of MM cell evolution in a drug resistant clone. We demonstrate that myeloma cells exposed to MM-adipocytes are rescued from dexamethasone-induced cell cycle arrest and have increased expression of FKBP5, a potential drug resistance gene. Our findings in patients confirm that BMAs are dynamic during myeloma disease progression (decrease during MM initiation, recover during disease remission) and that the interactions between BMAs and MM cells have previously unappreciated implications in the understanding and treatment of myeloma.
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Project description:FAM46C is one of the most recurrently mutated genes in multiple myeloma (MM), however its role in disease pathogenesis is not determined. Here we demonstrate that wild type (WT) FAM46C overexpression induces substantial cytotoxicity in MM cells. In contrast, FAM46C mutations found in MM patients abrogate this cytotoxicity indicating a MM survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP. Furthermore, pathway analysis suggests that enforced FAM46C expression activates the unfolded protein response (UPR) pathway and induces mitochondrial dysfunction. In contrast, endogenous CRISPR FAM46C depletion enhanced MM cell growth and notably decreasing Ig light chain and BIP expression, activating of ERK and anti-apoptotic signaling and conferring relative resistance to dexamethasone and lenalidomide treatment. The genes altered in FAM46C depleted cells are enriched for signaling pathways regulating estrogen, glucocorticoid, B cell receptor signaling and ATM signaling. Together these results implicate FAM46C in myeloma cell growth and survival. FAM46C mutation contributes to myeloma pathogenesis and disease progression by perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis.
2017-07-26 | GSE99357 | GEO
Project description:FAM46C is one of the most recurrently mutated genes in multiple myeloma (MM), however its role in disease pathogenesis is not determined. Here we demonstrate that wild type (WT) FAM46C overexpression induces substantial cytotoxicity in MM cells. In contrast, FAM46C mutations found in MM patients abrogate this cytotoxicity indicating a MM survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP. Furthermore, pathway analysis suggests that enforced FAM46C expression activates the unfolded protein response (UPR) pathway and induces mitochondrial dysfunction. In contrast, endogenous CRISPR FAM46C depletion enhanced MM cell growth and notably decreasing Ig light chain and BIP expression, activating of ERK and anti-apoptotic signaling and conferring relative resistance to dexamethasone and lenalidomide treatment. The genes altered in FAM46C depleted cells are enriched for signaling pathways regulating estrogen, glucocorticoid, B cell receptor signaling and ATM signaling. Together these results implicate FAM46C in myeloma cell growth and survival. FAM46C mutation contributes to myeloma pathogenesis and disease progression by perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis.
2017-07-26 | GSE99356 | GEO
Project description:Dysregulated oncogenic serine/threonine kinases play a pathological role in diverse forms of malignancies, including multiple myeloma (MM), and thus represent potential therapeutic targets. Here, we evaluated the biological and functional role of p21-activated kinase 4 (PAK4), and its potential as a new target in MM for clinical applications. PAK4 promoted MM cell growth and survival via activation of MM survival signaling pathways, including the MEK-ERK pathway. Furthermore, treatment with orally bioavailable PAK4 allosteric modulator (KPT-9274) significantly impacted MM cell growth and survival in a large panel of MM cell lines and primary MM cells alone and in the presence of bone marrow microenvironment. Intriguingly, we have identified FGFR3 as a novel binding partner of PAK4 and observed significant activity of KPT-9274 against t(4;14)-positive MM cells. These data support PAK4 as an oncogene in myeloma, and provide the rationale for the clinical evaluation of PAK4 modulator in myeloma.
2017-01-19 | GSE93745 | GEO
Project description:Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. The multiple myeloma SET domain (MMSET), identified by its fusion to the IgH locus in t(4;14) MM, is universally overexpressed and has been suggested to play an important role in tumorigenicity in t(4;14) MM. In order to identify downstream functional targets of MMSET, we knocked down MMSET expression with shRNAs in KMS11, a t(4;14) MM cell line, and identified differentially expressed genes by gene expression microarray analysis.
2014-07-16 | GSE59424 | GEO
Project description:Multiple Myeloma (MM) is a neoplasm of plasma cells originating in the bone marrow and is the second most common blood cancer in the United States. One challenge in understanding the pathogenesis of Multiple Myeloma (MM) and improving treatment is a lack of immunocompetent mouse models. We previously developed the IL6Myc mouse that generates plasmacytomas at 100% frequency that phenotypically resemble aggressive MM. Using comprehensive genomic analysis, we found that the RNA expression patterns between tumors were somewhat heterogenous, but nonetheless resembled MMSET (multiple myeloma SET domain), an aggressive form of human myeloma with poor prognosis. Cell lines derived from the mouse tumors expressed cell-surface markers typical of MM, but also expressed BAFF-R, which is infrequently found in human MM. The cell lines also had heterogeneous responses to chemotherapeutic drugs typically used to treat human MM. Interestingly IL6Myc tumors accumulated variants in genes like those seen in human MM, as well as recurrent Ig translocations, a common characteristic of human MM. These data indicate that the IL6Myc model is a useful model for aggressive MM that can be used to develop treatment and understand how early myc expression influences disease etiology.
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