JAK1/2 inhibitor therapy-associated lymphomas in myelofibrosis arising from a pre-existing B-cell clone
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA433197 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6677430.fastq.gz | Fastqsanger.gz | |||
| SRR6677431.fastq.gz | Fastqsanger.gz | |||
| SRR6677422.fastq.gz | Fastqsanger.gz | |||
| SRR6677432.fastq.gz | Fastqsanger.gz | |||
| SRR6677423.fastq.gz | Fastqsanger.gz |
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Project description:In this study, we elucidated differential gene expression between transformed and untransformed murine Stat1 -/- B cells by RNA sequencing. In addition, clinical samples from 2 lymphoma patients were analyzed. Key results are that 1) JAK1/2 inhibitor treatment in myelofibrosis is associated with an increased risk for aggressive B-cell lymphomas and 2) patients at risk can be identified by screening for pre-existing B-cell clones in peripheral blood or bone marrow.
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Project description:17 patients with myelofibrosis contributed paired research samples; the time points were pre-study and 12 weeks after commencing study treatment with CYT387.Gene expression analysis was investigated to study the effects of drug treatment. Additional analysis invesitigated differences in expression patterns in groups of anemia responders and non-responders following drug treatment. 34 samples representing 17 patients. Each patient submitted 1 pre-treatment sample and 1 post 12 weeks of treatment.
2013-01-14 | E-GEOD-40841 | biostudies-arrayexpress
Project description:Inhibition of Janus-kinase 1/2 (JAK1/2) is a mainstay to treat myeloproliferative neoplasms (MPN). Sporadic observations reported the co-incidence of B-cell non-Hodgkin lymphomas during treatment of MPN with JAK1/2 inhibitors. We assessed 626 patients with MPN, including 69 with myelofibrosis receiving JAK1/2 inhibitors for lymphoma development. B-cell lymphomas evolved in 4 (5.8%) of 69 patients receiving JAK1/2 inhibition compared with 2 (0.36%) of 557 with conventional treatment (16-fold increased risk). A similar 15-fold increase was observed in an independent cohort of 929 patients with MPN. Considering primary myelofibrosis only (N = 216), 3 lymphomas were observed in 31 inhibitor-treated patients (9.7%) vs 1 (0.54%) of 185 control patients. Lymphomas were of aggressive B-cell type, extranodal, or leukemic with high MYC expression in the absence of JAK2 V617F or other MPN-associated mutations. Median time from initiation of inhibitor therapy to lymphoma diagnosis was 25 months. Clonal immunoglobulin gene rearrangements were already detected in the bone marrow during myelofibrosis in 16.3% of patients. Lymphomas occurring during JAK1/2 inhibitor treatment were preceded by a preexisting B-cell clone in all 3 patients tested. Sequencing verified clonal identity in 2 patients. The effects of JAK1/2 inhibition were mirrored in Stat1-/- mice: 16 of 24 mice developed a spontaneous myeloid hyperplasia with the concomitant presence of aberrant B cells. Transplantations of bone marrow from diseased mice unmasked the outgrowth of a malignant B-cell clone evolving into aggressive B-cell leukemia-lymphoma. We conclude that JAK/STAT1 pathway inhibition in myelofibrosis is associated with an elevated frequency of aggressive B-cell lymphomas. Detection of a preexisting B-cell clone may identify individuals at risk.
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Project description:Myelofibrosis is a severe myeloproliferative neoplasm characterised by increased numbers of abnormal bone marrow megakaryocytes that induce fibrosis, destroying the hematopoietic microenvironment. To determine the cellular and molecular basis for aberrant megakaryopoiesis in myelofibrosis, we performed single-cell transcriptome profiling of 135,929 CD34+Lineage- hematopoietic stem/progenitor cells (HSPCs), single-cell proteomics, genomics and functional assays. We identified a bias towards megakaryocyte differentiation apparent from early multipotent stem cells in myelofibrosis and associated aberrant molecular signatures. A sub-fraction of myelofibrosis megakaryocyte progenitors (MkP) were transcriptionally similar to healthy-donor MkP but the majority were disease-specific, with distinct populations expressing fibrosis- and proliferation-associated genes. Mutant-clone HSPCs showed increased expression of megakaryocyte-associated genes compared to wild-type HSPCs, and we provide early validation of G6B as a potential immunotherapy target. Our study paves the way for selective targeting of the myelofibrosis clone and illustrates the power of single-cell multi-omics to discover tumor-specific therapeutic targets and mediators of tissue fibrosis.
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Project description:17 patients with myelofibrosis contributed paired research samples; the time points were pre-study and 12 weeks after commencing study treatment with CYT387.Gene expression analysis was investigated to study the effects of drug treatment. Additional analysis invesitigated differences in expression patterns in groups of anemia responders and non-responders following drug treatment.
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Project description:Myelofibrosis is a severe myeloproliferative neoplasm characterised by increased numbers of abnormal bone marrow megakaryocytes that induce progressive fibrosis, destroying the hematopoietic microenvironment. To determine the cellular and molecular basis for aberrant megakaryopoiesis in myelofibrosis, we performed high-throughput single-cell transcriptome profiling of 50,702 hematopoietic stem/progenitor cells (HSPCs), and single-cell proteomics, genomics and functional assays. We identified an aberrant pathway for direct megakaryocyte differentiation from the earliest stages of hematopoiesis in myelofibrosis and associated aberrant molecular signatures, including surface antigens selectively expressed by JAK2-mutant HSPCs. Myelofibrosis megakaryocyte progenitors were heterogeneous, with distinct expression of fibrosis and proliferation-associated genes and putative therapy targets. We validated the integrin G6B as a promising JAK2-mutant clone-specific surface antigen, warranting further development as an immunotherapeutic target. Our study paves the way for selective immunotherapeutic targeting in myelofibrosis and more broadly illustrates the power of single-cell multi-omics to discover tumor-specific therapeutic targets and mediators of tissue fibrosis.
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Project description:Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. Somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis; We used microarray to compare the gene expression profile of JAK1 mutation positive or negative ALL blasts Experiment Overall Design: Thawed or freshly isolated T-ALL cells (>90% blasts) were homogenized, total RNA was extracted and hybridized on Affymetrix microarrays
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Project description:The JAK family of non-receptor tyrosine kinases includes four subtypes (JAK1, JAK2, JAK3, and TYK2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immuno(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor subtype selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here, we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and TYK2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent transphosphorylation and cytokine signaling, while appearing to act largely as “silent” ligands for TYK2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented subtype selectivity.
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Project description:Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. Somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis We used microarray to compare the gene expression profile of JAK1 mutation positive or negative ALL blasts
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Project description:IL2 signals are transmitted through JAK1 and JAK3, but the transcriptomic consequences of each to the overall response is unclear. Here we analyzed the relative contribution of JAK1 and JAK3 to the NK cell IL2 response in vitro using titrated doses of isoform specific JAK inhibitors. Blockade of JAK1 and JAK3 have unequal effects on IL2-induced transcripts at pharmacologically relevant doses. Splenic NK cells were isolated by negative selection from 6wk old male C57BL/6 mice. These were cultured with IL2 (250U/ml) in the presence or absence of JAK1/3 inhibitors for 8hrs in vitro. Cells were then transferred directly into TriZol. RNA was prepared in Trizol for gene expression profiling by Affymetrix Mouse Gene 1.0 ST Arrays.
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