Abstract:Malignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T-cell–specific lymphoma model based on the human oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) translocation. We find that transformation of T cells shifts thymic cell populations to an undifferentiated immunophenotype, which occurs only after a period of latency, accompanied by induction of th… Show more
“…Similarly, STAT3, an important downstream modulator of NPM-ALK, was strongly activated as demonstrated by tyrosine phosphorylation in 8 week-old thymi, confirming that NPM-ALK activity is independent of PDGFRβ expression (Fig. S 1 D) [ 33 ]. Fig.…”
Background
Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRβ. Blocking PDGFRβ kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive.
Methods and results
In a transgenic mouse model that mimics PDGFRβ-driven human ALCL in vivo, we identify PDGFRβ as a driver of aggressive tumor growth. Mechanistically, PDGFRβ induces the pro-survival factor Bcl-xL and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo.
Conclusions
We therefore propose PDGFRβ as a novel biomarker and introduce PDGFRβ-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRβ or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK+ ALCL patients.
“…Similarly, STAT3, an important downstream modulator of NPM-ALK, was strongly activated as demonstrated by tyrosine phosphorylation in 8 week-old thymi, confirming that NPM-ALK activity is independent of PDGFRβ expression (Fig. S 1 D) [ 33 ]. Fig.…”
Background
Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRβ. Blocking PDGFRβ kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive.
Methods and results
In a transgenic mouse model that mimics PDGFRβ-driven human ALCL in vivo, we identify PDGFRβ as a driver of aggressive tumor growth. Mechanistically, PDGFRβ induces the pro-survival factor Bcl-xL and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo.
Conclusions
We therefore propose PDGFRβ as a novel biomarker and introduce PDGFRβ-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRβ or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK+ ALCL patients.
“…Redi E, et al discovered aberrant DNA methylation patterns in ALK + tumor cells, overlapping with regulatory regions, plus a high degree of epigenetic heterogeneity between individual tumors. This discrepancy might be associated with increasing of DNA methylation LINE-1 in NCI-H2228 in the presence of CBD [37].…”
A multitude of findings from the cell cultures and animal studies are available to support the anti-cancer properties of cannabinoids cannabidiol (CBD). Since CBD acts on multiple molecular targets, its clinical adaptation, especially in combination with cancer immunotherapy regimen remains a serious concern. Considering this, herein, we extensively studied the effect of CBD on the cytokine-induced killer (CIK) cells immunotherapy approach using multiple non-small cell lung cancer (NSCLC) cells harboring diverse genotypes. Our analysis showed that, a) CB2 receptor surface and intracellular expression increased significantly in NSCLC cells following co-culture with CIK cells, b) CBD exerts a pronounced synergistic effect on CIK-mediated lysis, resulting in a substantial increase in IFN-γ production, c) CBD explicitly promotes the CD25+CD69+ population and CD62L−CD45RA+ terminal effector memory (EMRA) population in NKT-CIK cells, suggesting an activation and effector memory T-cell differentiation. Of interest, we observed that clinically relevant CBD concentrations enhanced the calcium influx (mediated by the TRPV2 channel) and p-ERK expression directly in CIK cells, while in cancer cells it induced DNA double-strand breaks via upregulation of histone H2AX phosphorylation. Notably, the migration and invasion ability of NSCLC cells suppressed by CBD (in the absence of CIK cells) was rescued using the TRPV2 antagonist (Tranilast). We further investigated the epigenetic effects of this synergy and found that combining CBD with CIK cells decreased the LINE-1 mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation. Taken together, CBD holds a great potential for treating NSCLC with CIK cell immunotherapy and its complete success requires careful consideration of the patients' genetic background.
“…Redi E, et al discovered aberrant DNA methylation patterns in ALK + tumor cells, overlapping with regulatory regions, plus a high degree of epigenetic heterogeneity between individual tumors. This discrepancy might be associated with an increase of DNA methylation of LINE-1 in NCI-H2228 in the presence of CBD (59). Importantly, CBD alone had no effect on mRNA LINE-1 expression or p-rH2AX expression in CIK cells, suggesting CBD does not lead to genome instability or DNA damage in CIK cells.…”
IntroductionA multitude of findings from cell cultures and animal studies are available to support the anti-cancer properties of cannabidiol (CBD). Since CBD acts on multiple molecular targets, its clinical adaptation, especially in combination with cancer immunotherapy regimen remains a serious concern.MethodsConsidering this, we extensively studied the effect of CBD on the cytokine-induced killer (CIK) cell immunotherapy approach using multiple non-small cell lung cancer (NSCLC) cells harboring diverse genotypes.ResultsOur analysis showed that, a) The Transient Receptor Potential Cation Channel Subfamily V Member 2 (TRPV2) channel was intracellularly expressed both in NSCLC cells and CIK cells. b) A synergistic effect of CIK combined with CBD, resulted in a significant increase in tumor lysis and Interferon gamma (IFN-g) production. c) CBD had a preference to elevate the CD25+CD69+ population and the CD62L_CD45RA+terminal effector memory (EMRA) population in NKT-CIK cells, suggesting early-stage activation and effector memory differentiation in CD3+CD56+ CIK cells. Of interest, we observed that CBD enhanced the calcium influx, which was mediated by the TRPV2 channel and elevated phosphor-Extracellular signal-Regulated Kinase (p-ERK) expression directly in CIK cells, whereas ERK selective inhibitor FR180204 inhibited the increasing cytotoxic CIK ability induced by CBD. Further examinations revealed that CBD induced DNA double-strand breaks via upregulation of histone H2AX phosphorylation in NSCLC cells and the migration and invasion ability of NSCLC cells suppressed by CBD were rescued using the TRPV2 antagonist (Tranilast) in the absence of CIK cells. We further investigated the epigenetic effects of this synergy and found that adding CBD to CIK cells decreased the Long Interspersed Nuclear Element-1 (LINE-1) mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation. We further investigated the epigenetic effects of this synergy and found that adding CBD to CIK cells decreased the Long Interspersed Nuclear Element-1 (LINE-1) mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation.ConclusionsTaken together, CBD holds a great potential for treating NSCLC with CIK cell immunotherapy. In addition, we utilized NSCLC with different driver mutations to investigate the efficacy of CBD. Our findings might provide evidence for CBD-personized treatment with NSCLC patients.
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