Gene expression profiling signatures allow the identification of unclassifiable leukemic B-cell lymphoid neoplasms
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE79196 | GEO | 2018/02/13
REPOSITORIES: GEO
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Project description:Gene expression profile (GEP) was analyzed in bone marrow (BM) samples from patients with leukemia or leukemic phase of lymphoma at different time points following aspiration. Among numerous changes in GEP evolved over time a discrete subset of > 60 genes exhibited prompt and sustained switch in expression consistently. Similar results were discovered recently in BM samples from patients with multiple myeloma (GSE36036). GEP was also examined in peripheral blood as well as in BM samples depleted of red blood cells (=WBC) and in cultured cells from some of the patients.
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Project description:Small B-cell lymphoid neoplasms (SBCLNs) are a heterogeneous group of diseases characterized by malignant clonal proliferation of mature B-cells. However, the classification of SBCLNs remains a challenge, especially in cases where histopathological analysis is unavailable or those with atypical laboratory findings or equivocal pathologic data. In this study, gene expression profiling of 1,039 samples from 27 GEO datasets was first investigated to select highly and differentially expressed genes among SBCLNs. Samples from 57 SBCLN cases and 102 nonmalignant control samples were used to train a classifier using the NanoString platform. The classifier was built by employing a cascade binary classification method based on the random forest algorithm with 35 refined gene signatures. Cases were successively classified as chronic lymphocytic leukemia/small lymphocytic lymphoma, conventional mantle cell lymphoma, follicular lymphoma, leukemic non-nodal mantle cell lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia, and other undetermined. The classifier algorithm was then validated using an independent cohort of 197 patients with SBCLNs. Under the distribution of our validation cohort, the overall sensitivity and specificity of proposed algorithm model were >95% respectively for all the cases with tumor cell content greater than 0.72. Combined with additional genetic aberrations including IGH-BCL2 translocation, MYD88 L265P mutation, and BRAF V600E mutation, the optimal sensitivity and specificity were respectively found at 0.88 and 0.98. In conclusion, the established algorithm demonstrated to be an effective and valuable ancillary diagnostic approach for the sub-classification and pathologic investigation of SBCLN in daily practice.
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Project description:Gene expression profile (GEP) was analyzed in bone marrow (BM) samples from patients with leukemia or leukemic phase of lymphoma at different time points following aspiration. Among numerous changes in GEP evolved over time a discrete subset of > 60 genes exhibited prompt and sustained switch in expression consistently. Similar results were discovered recently in BM samples from patients with multiple myeloma (GSE36036). GEP was also examined in peripheral blood as well as in BM samples depleted of red blood cells (=WBC) and in cultured cells from some of the patients. Comparative gene expression profiling of whole bone marrow samples from patients with leukemia fixed either immediately following aspiration or after delayed RNA fixation. Comparison was also made between cultured bone marrow cells fixed immediately following spread from the bottom well versus after maintenance in suspension (for 120 minutes).
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Project description:Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing chronic inflammation, tissue destruction, severe infections and sepsis, all linked to poor quality of life and high mortality. Despite numerous sequencing efforts in L-CTCL, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analysis with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. In order to examine IQDMA-specific effects in an unbiased and dose-dependent manner without limiting the analysis to only kinases, we carried out global proteomics profiling in SeAx cells after 24 h treatment with 1, 2.5 and 10 µM IQDMA. The differential proteins affected in response to increasing IQDMA concentrations were found to be related to multiple cellular processes in metabolism, ribosomal RNA processing/modification, protein translation, and surprisingly keratinization.. Dual inhibition of STAT3/5 using small molecule degraders abolished L-CTCL cell growth in vitro. Furthermore, upstream broad range kinase targeting through IQDMA, a newly classified multi-kinase inhibitor, revealed a pharmacologic opportunity to alternatively block the STAT3/5 pathway by inhibiting the PAK2 serine/threonine kinase, which was very effective in patient cells carrying STAT3/5 copy number gains and in vivo in reducing tumor growth and disease dissemination in an intradermal xenograft mouse model. In summary, we conclude that STAT3/5 and PAK2 are new therapy targets to be further explored in L-CTCL.
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Project description:Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing chronic inflammation, tissue destruction, severe infections and sepsis, all linked to poor quality of life and high mortality. Despite numerous sequencing efforts in L-CTCL, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analysis with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. In order to examine IQDMA-specific effects in an unbiased and dose-dependent manner without limiting the analysis to only kinases, we carried out global proteomics profiling in SeAx cells after 24 h treatment with 1, 2.5 and 10 µM IQDMA. The differential proteins affected in response to increasing IQDMA concentrations were found to be related to multiple cellular processes in metabolism, ribosomal RNA processing/modification, protein translation, and surprisingly keratinization.. Dual inhibition of STAT3/5 using small molecule degraders abolished L-CTCL cell growth in vitro. Furthermore, upstream broad range kinase targeting through IQDMA, a newly classified multi-kinase inhibitor, revealed a pharmacologic opportunity to alternatively block the STAT3/5 pathway by inhibiting the PAK2 serine/threonine kinase, which was very effective in patient cells carrying STAT3/5 copy number gains and in vivo in reducing tumor growth and disease dissemination in an intradermal xenograft mouse model. In summary, we conclude that STAT3/5 and PAK2 are new therapy targets to be further explored in L-CTCL.
2022-10-06 | PXD035699 | Pride
Project description:We created a mouse model where conditional expression of physiologic levels of an Mll-AF4 fusion oncogene induces development of acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Immunophenotypic and gene expression analysis of the ALL cells demonstrated bone marrow replacement with B-precursor cells which express a gene expression profile that has significant overlap with profiles in human MLL-rearranged ALL. Experiment Overall Design: Total RNA from normal pro-B, pre-B, immature B and mature B lymphocytes, and from leukemic pre-B cells was isolated and hybridized to Affymetrix expresison microarrays.
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2023-09-01 | GSE237299 | GEO
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Project description:Mutation patterns associated with leukemic transformation of MPN
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