Molecular signatures for Hairy cell leukemia
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ABSTRACT:
PROVIDER: PRJNA676121 | ENA |
REPOSITORIES: ENA
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Project description:Analysis of the expression profile of 298 mRNA's, measured with the nCounter (Nanostring Technologies platform), in 13 samples from the peripheral blood of Hairy cell leukemia patients Hairy cell leukemia (HCL) is a rare chronic B-cell malignancy, characterized by infiltration of bone marrow, blood and spleen by typical “hairy cells” that bear the BRAFV600E mutation. However, in addition to the intrinsic activation of the MAP kinase pathway as a consequence of the BRAFV600E mutation, the potential participation of other signaling pathways to the pathophysiology of the disease remains unclear. Using mRNA gene expression profiling based on the Nanostring technology and the analysis of 290 genes with crucial roles in B-cell lymphomas, we defined a 17 gene expression signature specific for HCL. Our analysis revealed intrinsic activation of the non-canonical NF-B pathway with underexpression of BIRC2 and BIRC3, two specific non-canonical NF-B inhibitors. Western blots confirmed activation of this pathway with increased processing of p100 in primary HCL samples. Separate analysis of samples from classical and variant forms of hairy cell leukemia showed almost similar mRNA expression profiles apart from overexpression in vHCL of the immune checkpoints CD274 and PDCD1LG2 and underexpression of FAS. Our results provide a better understanding of the pathogenesis of HCL and describe new and potential targets for treatment approaches and guidance for studies in the molecular mechanisms of HCL.
2020-11-12 | GSE161279 | GEO
Project description:The hairy cell leukemia line JOK1 with low RhoH expression was stably trasfected with either an empty expression vector or this same vector expressing human RhoH. The transcriptomes of these two daughter lines were then compared by differential microarray analysis The hairy cell leukemia line JOK1 with low RhoH expression was stably trasfected with either an empty expression vector or this same vector expressing human RhoH. The transcriptomes of these two daughter lines were then compared by differential microarray analysis
2021-01-03 | GSE156483 | GEO
Project description:Hairy Cell Leukemia Cell Line JOK1 +/- RhoH Reconstitution
| PRJNA658103 | ENA
Project description:Hairy cell leukemia (HCL) shows unique clinico-pathological and biological features. HCL responds well to purine analogues but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL. Here, we investigated the biological and therapeutic importance of the activated BRAF-MEK-ERK pathway in HCL by exposing in vitro primary leukemic cells purified from 26 patients to clinically available BRAF (Vemurafenib; Dabrafenib) or MEK (Trametinib) inhibitors. Results were validated in vivo in samples from Vemurafenib-treated HCL patients within a phase-2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression signature, downregulation of the HCL markers CD25, TRAP and cyclin-D1, smoothening of leukemic cells' hairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by co-culture with bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This protective effect could be counteracted by combined BRAF and MEK inhibition. Our results strongly support and inform the clinical use of BRAF and MEK inhibitors in HCL.
2014-12-12 | GSE63790 | GEO
Project description:Hairy cell leukemia (HCL) shows unique clinico-pathological and biological features. HCL responds well to purine analogues but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL. Here, we investigated the biological and therapeutic importance of the activated BRAF-MEK-ERK pathway in HCL by exposing in vitro primary leukemic cells purified from 26 patients to clinically available BRAF (Vemurafenib; Dabrafenib) or MEK (Trametinib) inhibitors. Results were validated in vivo in samples from Vemurafenib-treated HCL patients within a phase-2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression signature, downregulation of the HCL markers CD25, TRAP and cyclin-D1, smoothening of leukemic cells' hairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by co-culture with bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This protective effect could be counteracted by combined BRAF and MEK inhibition. Our results strongly support and inform the clinical use of BRAF and MEK inhibitors in HCL. Analysis of differential gene expression in primary leukemic cells purified from peripheral blood of 6 HCL patients (from A to F), treated with Vemurafenib 1000 nM, in comparison with vehicle-treated (DMSO) HCL cells, for 48 hours or/and 72 hours. 24 gene expression profiles were analysed.
2014-12-12 | E-GEOD-63790 | biostudies-arrayexpress
Project description:<p>To understand the genetic mechanisms driving variant and IGHV4-34 expressing hairy-cell leukemia, we performed whole exome sequencing of tumor/normal pairs from ten patients.</p>
| phs000671.v1.p1 | EGA
Project description:<p>To understand the genetic mechanisms driving variant and IGHV4-34 expressing hairy-cell leukemia, we performed whole exome sequencing of tumor/normal pairs from ten patients.</p>
| phs000671 | dbGaP
Project description:The objectives of this study encompassed a thorough exploration of the potential implications of protein profiling in hairy roots, specifically focusing on optimizing and enhancing C. asiatica organ cell biofactories. In this pursuit, we categorized established C. asiatica hairy root lines according to their capacity for centelloside production, classifying them into HIGH, MID, or LOW categories. For comparative analysis, wild adventitious (Adv) roots were extracted from in vitro C. asiatica seedlings and cultivated in solid MS medium at 25°C in complete darkness, serving as control specimens. This meticulous, label-free proteomic analysis enabled the successful identification of several proteins. Our research substantially builds upon and extends the findings presented by Alcalde et al. (2022) (DOI: 10.3389/fpls.2022.1001023). In their study, distinctive morphological and metabolic variations were noted among different C. asiatica hairy root lines. Such differences are presumably attributable to the random incorporation of a selective set of genes from the T-DNA, with particular emphasis on the rol and aux genes.
2024-01-26 | PXD045705 | Pride
Project description:Hairy cell leukemia (HCL) is a B-cell malignancy that in its classic form is exquisitely sensitive to single-agent purine analog therapy, but that is associated in many patients with late relapse and eventual purine analog resistance. Minimal residual disease, which is present in most patients achieving complete remission with purine analogs, retains Ags that are ideal for targeted therapy. Rituximab, which targets CD20, is active as a single agent, particularly if combined with purine analogs. Recombinant immunotoxins targeting either CD25 or CD22 and containing truncated Pseudomonas exotoxin have achieved major responses in relapsed/refractory HCL. Moxetumomab pasudotox in phase 1 testing achieved responses in 86% of such patients (complete in 46%) without dose limiting toxicity and often without MRD. Soluble CD22 has been used for improved detection and monitoring of HCL, particularly the poor-prognosis variant that lacks CD25. Ig rearrangements unique for each HCL patient have been cloned, sequenced, and followed by real-time quantitative PCR using sequence-specific reagents. Analysis of these rearrangements has identified an unmutated IGVH4-34-expressing poor-prognosis variant with immunophenotypic characteristics of either classic or variant HCL. The BRAF V600E mutation, reported in 50% of melanomas, is present in > 85% of HCL cases that are both classic and express rearrangements other than IGVH4-34, making HCL a potential target for specific inhibitors of BRAF V600E. Additional targets are being defined in both classic and variant HCL, which should improve both detection and therapy.
| S-EPMC6290482 | biostudies-other
Project description:ERG is an Ets-transcription factor required for normal blood stem cell development. High ERG expression in acute myeloid leukemia (AML) and acute T-cell lymphoblastic leukemia (T-ALL) is associated with a stem cell signature and poor prognosis. In murine over-expression models, human ERG is a potent oncogene that induces both T-ALL and AML. However the functional and molecular consequences of high ERG expression in normal hematopoietic stem/progenitors (HSPCs), and how this contributes to leukemia development, are unknown. Here we show that retroviral transduction of ERG into human CD34+ cells and maintenance of ERG at levels present in high ERG AML results in altered myeloid and T cell differentiation and an increase in the self-renewal capacity of transduced progenitors but not the more primitive stem cell compartment. Integrated analysis of genome-wide expression in high ERG CD34+ and ERG binding profiles in HSPCs revealed that these functional characteristics were accompanied by an expression signature that was enriched in normal HSCs, high ERG AMLs, early T-cell precursor (ETP)-ALLs and leukemic stem cell signatures associated with poor clinical outcome. The proliferative advantage of high ERG progenitors may provide a cellular context for the acquisition and propagation of mutations that contribute to the pathogenesis of leukaemia. RNA sequencing in ERG overexpressing human CD34+ cells
2014-10-31 | E-GEOD-53665 | biostudies-arrayexpress