The histone deacetylase inhibitor givinostat (ITF2357) exhibits potent anti-tumor activity against CRLF2-rearranged BCP-ALL.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE77270 | GEO | 2017/03/24
SECONDARY ACCESSION(S): PRJNA309937
REPOSITORIES: GEO
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Project description:Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia We report two novel, cryptic chromosomal abnormalities in precursor B-cell acute lymphoblastic leukemia (BCP-ALL): a translocation, either t(X;14)(p22;q32) or t(Y;14)(p11;q32), in 33 patients and an interstitial deletion, either del(X)(p22.33p22.33) or del(Y)(p11.32p11.32), in 64 patients, involving the pseudoautosomal region (PAR1) of the sex chromosomes. The incidence of these abnormalities was 5% in childhood ALL (0.8% with the translocation, 4.2% with the deletion). Patients with the translocation were older (median age 16 years), whilst the patients with the deletion were younger (median age 4 years). The two abnormalities result in deregulated expression of the cytokine receptor, cytokine receptor-like factor 2, CRLF2 (also known as thymic stromal-derived lymphopoietin receptor, TSLPR). Over-expression of CRLF2 was associated with activation of the JAK-STAT pathway in cell lines and transduced primary B-cell progenitors, sustaining their proliferation and indicating a causal role of CRLF2 over-expression in lymphoid transformation. In Down Syndrome (DS) ALL and two non DS BCP-ALL cell lines, CRLF2 deregulation was associated with mutations of the JAK2 pseudokinase domain suggesting oncogenic cooperation, as well as highlighting a link between non DS ALL and JAK2 mutations. Keyword(s): Global copy number analysis using Agilent oligonucleotide arrays
2009-07-18 | GSE17165 | GEO
Project description:Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia We report two novel, cryptic chromosomal abnormalities in precursor B-cell acute lymphoblastic leukemia (BCP-ALL): a translocation, either t(X;14)(p22;q32) or t(Y;14)(p11;q32), in 33 patients and an interstitial deletion, either del(X)(p22.33p22.33) or del(Y)(p11.32p11.32), in 64 patients, involving the pseudoautosomal region (PAR1) of the sex chromosomes. The incidence of these abnormalities was 5% in childhood ALL (0.8% with the translocation, 4.2% with the deletion). Patients with the translocation were older (median age 16 years), whilst the patients with the deletion were younger (median age 4 years). The two abnormalities result in deregulated expression of the cytokine receptor, cytokine receptor-like factor 2, CRLF2 (also known as thymic stromal-derived lymphopoietin receptor, TSLPR). Over-expression of CRLF2 was associated with activation of the JAK-STAT pathway in cell lines and transduced primary B-cell progenitors, sustaining their proliferation and indicating a causal role of CRLF2 over-expression in lymphoid transformation. In Down Syndrome (DS) ALL and two non DS BCP-ALL cell lines, CRLF2 deregulation was associated with mutations of the JAK2 pseudokinase domain suggesting oncogenic cooperation, as well as highlighting a link between non DS ALL and JAK2 mutations. Keyword(s): Global copy number analysis using Agilent oligonucleotide arrays DNA copy number analysis of 16 acute lymphoblastic leukaemia samples (13 diagnostic, 1 diagnostic and relapse pair and 2 cell-lines) was performed using Agilent 244K and 105K custom microarrays. These samples were hybridised against gender matched reference DNA.
2010-05-16 | E-GEOD-17165 | biostudies-arrayexpress
Project description:CRLF2 rearranged Ph-like ALL cells are driven by oncogenic cytokine receptor signaling mediated by CRLF2 and JAK2. MHH-cALL4 cells were treated with ruxolotinib (JAK2 inhibitor) to provide insight into mechanisms of drug resistance.
2020-05-28 | GSE132486 | GEO
Project description:CRLF2-rearranged acute lymphoblastic leukemia (ALL) is associated with poor clinical outcomes. Although JAK1/2 is activated in this type of ALL, treatment with JAK1/2 inhibitors is insufficient in inhibiting cell growth and inducing apoptosis. BCL6 upregulation upon JAK inhibition may account for this insufficiency. Therefore, we compared gene expression changes of two CRLF2-rearranged ALL cell lines, MHH-CALL-4 and MUTZ-5, treated with either ruxolitinib(a JAK1/2 inhibitor), FX1(a BCL6 inhibitor), their combination, or control.
2022-07-31 | E-MTAB-10755 | biostudies-arrayexpress
Project description:Deregulated expression of the type I cytokine receptor, CRLF2 (CRLF2-d), is observed in 5-15% of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), is associated with activation of the JAK/STAT pathway and has an inferior outcome compared to those with good risk cytogenetics. We aimed to determine the clinical and genetic landscape of CRLF2-d ALL using genomic approaches including karyotyping, fluorescence in situ hybridisation, whole genome and whole exome sequencing. The clinical and demographic features of CRLF2-d patients were characteristic of BCP-ALL. Patients with IGH-CRLF2 were older than those with P2RY8-CRLF2 (4yrs v 14yrs, p<0.001), while the incidence of CRLF2-d among Down syndrome patients was high (31%). CRLF2-d co-occurred with established primary chromosomal rearrangements but the majority (72%) had B-other ALL. The copy number alteration (CNA) profile was similar to B-other ALL, although CRLF2-d patients harboured higher frequencies of IKZF1 (43% v 23%) and BTG1 deletions (15% v 2%). There were differences in the CNA profile between IGH-CRLF2 and P2RY8-CRLF2 patients: deletions of IKZF1 (71% v 33% p<0.001), BTG1 (31% v 9%, p=0.004) and ADD3 (46% v 13%, p=0.008). A novel gene fusion, USP9X-DDX3X was discovered in 18% of CRLF2-d ALL. Pathway analysis of the mutational profile revealed novel involvement of the focal adhesion pathway. In conclusion, CRLF2-d defines a discrete subtype of B-other ALL, characterised by a distinctive profile of cooperating abnormalities, which drive leukaemogenesis in conjunction with CRLF2-d. Although the functional relevance of many of these abnormalities are unknown, they likely activate alternative pathways, which may represent novel therapeutic targets. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved diagnostic bone marrow or remission bone marrow.
2017-02-24 | GSE83272 | GEO
Project description:The histone deacetylase inhibitor givinostat (ITF2357) exhibits potent anti-tumor activity against CRLF2-rearranged BCP-ALL.
| PRJNA309937 | ENA
Project description:The cytokine TSLP stimulates in vitro proliferation of human fetal B cell progenitors. Genetic alterations that cause overexpression of the TSLP receptor component, CRLF2, lead to B cell acute lymphoblastic leukemia (CRLF2 B-ALL) with poor outcome. The in vivo role of TSLP in normal human B cell development and its contribution to CRLF2 B-ALL are unknown. In classic xenograft models CRLF2-mediated signaling is unlikely to be activated by mouse TSLP, based on data from engineered cellular models. Here, we show that mouse TSLP does not induce activation of the CRLF-2 downstream pathways (JAK/STAT and AKT/mTOR) that are induced by human TSLP (hTSLP) in CRLF2 B-ALL cells. Based on this, we developed a novel human-mouse xenograft model system comprised of mice that produce hTSLP (+T mice) to activate human CRLF2-mediated signaling and mice that lack hTSLP (–T mice). Normal serum levels of hTSLP were achieved in +T mice, while hTSLP was undetectable in –T mice. hTSLP produced by stroma induced JAK/STAT and AKT/mTOR pathway activation and showed functional in vivo effects on normal human B cell progenitors and primary CRLF2 B-ALL cells. Whole genome microarray of primary CRLF2 B-ALL showed an induction of mTOR regulated gene expression and preservation of TSLP responsiveness in cells expanded in +T mice as compared to –T mice.
2016-05-03 | GSE65274 | GEO
Project description:To investigate the different susceptibility to relapse, CRLF2-overexpressing cases with and without P2RY8-CRLF2 fusion were analyzed by next-generation sequencing based gene expression profiling.
2016-08-30 | E-MTAB-4737 | biostudies-arrayexpress
Project description:Seventeen T-ALL patients out of 120 (14.2%) presented CRLF2 expression 5 times higher than the median (‘CRLF2-high’) with a significantly inferior 5-y EFS and an increased CIR compared to CRLF2-low patients.GEP of 15 T-ALL patients with (‘CRLF2-high’) were compared to 15 CRLF2-low patients. GSEA identified cell cycle deregulating gene sets.
2017-03-01 | GSE72623 | GEO
Project description:Relapsed/refractory Hodgkin lymphoma (HL) is an unmet medical need requiring new therapeutic options. Interactions between the histone deacetylase inhibitor Givinostat and the RAF/MEK/ERK inhibitor Sorafenib were examined in HDLM-2 and L-540 HL cell lines. Exposure to Givinostat/Sorafenib induced a synergistic inhibition of cell growth (range, 70- 80%) and a dramatic increase in cell death (up to 96%) due to increased H3 and H4 acetylation and strong mitochondrial injury. Gene expression profiling indicated that the synergistic effects of Givinostat/Sorafenib treatment are associated with the modulation of cell cycle and cell death pathways. Exposure to Givinostat/Sorafenib resulted in sustained production of reactive oxygen species (ROS) and activation of necroptotic cell death. The necroptosis inhibitor Necrostatin-1 prevented Givinostat/Sorafenib-induced ROS production, mitochondrial injury, activation of BH3-only protein BIM and cell death. Knockdown experiments identified BIM as a key signaling molecule that mediates Givinostat/Sorafenib-induced oxidative death of HL cells. Furthermore, in vivo xenograft studies demonstrated a 50% reduction in tumor burden (P < 0.0001), a 5- to 15-fold increase in BIM expression (P M-bM-^IM-$.0001) and a 4-fold increase in tumor necrosis in Givinostat/Sorafenib-treated animals compared to mice that received the single agents. These results provide a rationale for exploring Givinostat/Sorafenib combination in relapsed/refractory HL. The Hodgkin lymphoma cell line L-540 was obtained from the DSMZ (Braunschweig, Germany, EU). Cells were routinely maintained in RPMI medium 1640 (Lonza, Basel, Switzerland) supplemented with 20% FBS (Lonza) and 2 mM glutamine (Lonza). Cells were maintained at 37M-BM-0C in a water-saturated atmosphere of 5% CO2 in air. 10x10^6 L-540 cells were seeded in 75 cm2 flask and, after 24 hrs, cells were treated with 100 nM Givinostat (Italfarmaco SpA, Milan, Italy, EU) and/or 5 M-BM-5M sorafenib (Bayer, Berlin,M-bM-^@M-(Germany, EU) in culture medium for 24 hours. At the end of treatment, cells were collected and RNA was extracted.
2015-03-01 | E-GEOD-65483 | biostudies-arrayexpress