The Follicular Lymphoma and Chronic Lymphocytic Leukemia Proliferative Microenvironment at Single-Cell Resolution
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE261917 | GEO | 2024/11/19
REPOSITORIES: GEO
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Project description:Epigenetic code modifications by histone deacetylase inhibitors (HDACi) have recently been proposed as potential new therapies for hematological malignancies. Chronic Lymphocytic Leukemia (CLL) remains incurable despite the introduction of new treatments. CLL cells are characterized by an apoptosis defect rather than excessive proliferation, but proliferation centers have been found in organs such as bone marrow and lymph nodes. Here, we investigated gene expression modifications in CLL cells following treatment with valproic acid (VPA), a well-tolerated anti-epileptic drug with HDAC inhibitory activity.
2009-08-24 | GSE14973 | GEO
Project description:Epigenetic code modifications by histone deacetylase inhibitors (HDACi) have recently been proposed as potential new therapies for hematological malignancies. Chronic Lymphocytic Leukemia (CLL) remains incurable despite the introduction of new treatments. CLL cells are characterized by an apoptosis defect rather than excessive proliferation, but proliferation centers have been found in organs such as bone marrow and lymph nodes. Here, we investigated gene expression modifications in CLL cells following treatment with valproic acid (VPA), a well-tolerated anti-epileptic drug with HDAC inhibitory activity. Experiment Overall Design: CLL cells obtained from 14 patients were treated in vitro with a concentration of 1mM VPA for 4 hours. VPA effects on gene expression were thereafter studied using Affymetrix technology
2009-09-17 | E-GEOD-14973 | biostudies-arrayexpress
Project description:PIM serine/threonine kinases are overexpressed, translocated or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types, and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBLC), follicular lymphoma (FL), marginal zone lymphoma-MALT type (MZL-MALT), chronic lymphocytic leukemia (CLL) and nodal marginal zone lymphoma (NMZL) cases. Increased PIM2 protein expression was associated with an aggressive clinical course in ABC-DLBCL patients. Pharmacological and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4E-BP1(Ser65) as molecular biomarkers characteristic of PIM2 activity, and indicated the involvement of PIM2 kinase in regulating mTORC1. The simultaneous genetic inhibition of all three PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification. Gene-expression profiling was conducted in a series of 114 B-cell non-Hodgkin lymphoma patients (DLBCL, FL, MALT, MCL, CLL and NMZL). Seven freshly frozen lymph nodes and six freshly frozen reactive tonsils were used as controls.
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Project description:Understanding the crosstalk between malignant B-cells and their milieu could provide clues on the molecular and clinical biology of Chronic Lymphocytic Leukemia (CLL). Aiming to generate novel therapeutic strategies, different groups have studied different CLL proliferative fractions. We previously, identified one of these proliferative subsets in the peripheral blood from progressive unmutated CLL patients. Since the presence of this small subset appears to be a hallmark of a proliferative disease in which B lymphocytes are being constitutively activated in the proliferative centers of these patients, we performed gene expression analysis comparing the global mRNA and microRNAs expression of this leukemic subpopulation. Our results suggest that the proliferative behaviour of this fraction appears to depend on microRNA-22 over-expression, which induces PTEN downregulation and PI3K/AKT pathway activation. Transfection experiments demonstrated that miR-22 overexpression in CLL B-cells switches on PI3K/AKT leading to FOXO1 inactivation, p27-Kip1 downregulation, and overexpression of Survivin and Ki-67 proteins. We also demonstrated that this pathway could be triggered by microenvironment signals like CD40L/IL4 and more importantly, that this regulatory loop is also present in lymph nodes from progressive UM patients. Altogether, these results underline the key role of PI3K/AKT pathway in the generation of the CLL proliferative pool and provide rationale for the usage of PI3K inhibitors. Two-subset of B cells, QF vs PF. 8 samples of 4 patients.
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Project description:Understanding the crosstalk between malignant B-cells and their milieu could provide clues on the molecular and clinical biology of Chronic Lymphocytic Leukemia (CLL). Aiming to generate novel therapeutic strategies, different groups have studied different CLL proliferative fractions. We previously, identified one of these proliferative subsets in the peripheral blood from progressive unmutated CLL patients. Since the presence of this small subset appears to be a hallmark of a proliferative disease in which B lymphocytes are being constitutively activated in the proliferative centers of these patients, we performed gene expression analysis comparing the global mRNA and microRNAs expression of this leukemic subpopulation. Our results suggest that the proliferative behaviour of this fraction appears to depend on microRNA-22 over-expression, which induces PTEN downregulation and PI3K/AKT pathway activation. Transfection experiments demonstrated that miR-22 overexpression in CLL B-cells switches on PI3K/AKT leading to FOXO1 inactivation, p27-Kip1 downregulation, and overexpression of Survivin and Ki-67 proteins. We also demonstrated that this pathway could be triggered by microenvironment signals like CD40L/IL4 and more importantly, that this regulatory loop is also present in lymph nodes from progressive UM patients. Altogether, these results underline the key role of PI3K/AKT pathway in the generation of the CLL proliferative pool and provide rationale for the usage of PI3K inhibitors.
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