A novel model of alternative NF-κB pathway activation in anaplastic large cell lymphoma

Wang, Hongbo; Wei, Wei; Jp, Zhang; Song, Zhihui; Li, Yangyang; Xiao, Wenming; Liu, Yijun; Zeng, Mu‐Sheng; Petrus, Michael; Thomas, Craig J.; Kadin, Marshall E.; Nakagawa, Masao; Waldmann, Thomas A.; Yang, Yibin

doi:10.1038/s41375-020-01088-y

Cited by 18 publications

(16 citation statements)

References 44 publications

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“…Although ALK expression has also been reported in chronic lymphoblastic leukemia and anaplastic large cell T lymphoma [22,23], it is not common in acute myeloid leukemia and chronic myeloid leukemia or multiple myeloma. Thus, ALK inhibition alone hardly explains the remarkably high sensitivity of our leukemia and multiple myeloma cell lines to crizotinib.…”

Section: Discussionmentioning

confidence: 99%

Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells

et al. 2021

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Crizotinib was a first generation of ALK tyrosine kinase inhibitor approved for the treatment of ALK-positive non-small-cell lung carcinoma (NSCLC) patients. COMPARE and cluster analyses of transcriptomic data of the NCI cell line panel indicated that genes with different cellular functions regulated the sensitivity or resistance of cancer cells to crizotinib. Transcription factor binding motif analyses in gene promoters divulged two transcription factors possibly regulating the expression of these genes, i.e., RXRA and GATA1, which are important for leukemia and erythroid development, respectively. COMPARE analyses also implied that cell lines of various cancer types displayed varying degrees of sensitivity to crizotinib. Unexpectedly, leukemia but not lung cancer cells were the most sensitive cells among the different types of NCI cancer cell lines. Re-examining this result in another panel of cell lines indeed revealed that crizotinib exhibited potent cytotoxicity towards acute myeloid leukemia and multiple myeloma cells. P-glycoprotein-overexpressing CEM/ADR5000 leukemia cells were cross-resistant to crizotinib. NCI-H929 multiple myeloma cells were the most sensitive cells. Hence, we evaluated the mode of action of crizotinib on these cells. Although crizotinib is a TKI, it showed highest correlation rates with DNA topoisomerase II inhibitors and tubulin inhibitors. The altered gene expression profiles after crizotinib treatment predicted several networks, where TOP2A and genes related to cell cycle were downregulated. Cell cycle analyses showed that cells incubated with crizotinib for 24 h accumulated in the G2M phase. Crizotinib also increased the number of p-H3(Ser10)-positive NCI-H929 cells illustrating crizotinib’s ability to prevent mitotic exit. However, cells accumulated in the sub-G0G1 fraction with longer incubation periods, indicating apoptosis induction. Additionally, crizotinib disassembled the tubulin network of U2OS cells expressing an α-tubulin-GFP fusion protein, preventing migration of cancer cells. This result was verified by in vitro tubulin polymerization assays. In silico molecular docking also revealed a strong binding affinity of crizotinib to the colchicine and Vinca alkaloid binding sites. Taken together, these results demonstrate that crizotinib destabilized microtubules. Additionally, the decatenation assay showed that crizotinib partwise inhibited the catalytic activity of DNA topoisomerase II. In conclusion, crizotinib exerted kinase-independent cytotoxic effects through the dual inhibition of tubulin polymerization and topoisomerase II and might be used to treat not only NSCLC but also multiple myeloma.

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Section: Discussionmentioning

confidence: 99%

Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells

et al. 2021

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“…On the other hand, non-canonical NF-kB signaling is activated downstream of CD30 in CD30 + PTCL 33 . In ALCL, RelB enhances transcriptional activation by NFKB2-ROS1 gene fusions 12 and STAT3 drives the expression of CD30 and NFKB2 34 . Overexpression of GAPDH in T cells, leads to a PTCL-TFH-like disease in mice which is largely driven by non-canonical NF-kB signaling 35 .…”

Section: Discussionmentioning

confidence: 99%

FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T cell lymphoma, not otherwise specified

Debackere¹,

Marcelis²,

Demeyer³

et al. 2021

Preprint

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Peripheral T cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Up to 30% of PTCL lack distinctive features and are classified as PTCL, not otherwise specified (PTCL-NOS). To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we performed RNA-sequencing of 18 cases and validated results in an independent cohort of 37 PTCL cases. We identified FYN-TRAF3IP2, KHDRBS1-LCK and SIN3A-FOXO1 as new in-frame fusion transcripts, with FYN-TRAF3IP2 as a recurrent fusion detected in 8 of 55 cases. Using ex vivo and in vivo experiments, we demonstrate that FYN-TRAF3IP2 and KHDRBS1-LCK activate signaling pathways downstream of the T cell receptor (TCR) complex and confer therapeutic vulnerability to clinically available drugs.

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“…In addition, as JAK/STAT3 mutations promoted STAT3-based transcription activation and directly regulated NF-κB and CD30 levels in NIK+/ALK-ALCL, combined NIK and JAK inhibitor therapy could be applied to benefit patients [165]. JAK inhibitor AZD1480 treatment potently blocked STAT phosphorylation but yielded no anti-proliferative effects in cHL, as it led to ERK1/2 phosphorylation upregulation.…”

Section: Combinational Therapymentioning

confidence: 99%

Janus Kinase Signaling: Oncogenic Criminal of Lymphoid Cancers

Wan

et al. 2021

Cancers

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The Janus kinase (JAK) family are known to respond to extracellular cytokine stimuli and to phosphorylate and activate signal transducers and activators of transcription (STAT), thereby modulating gene expression profiles. Recent studies have highlighted JAK abnormality in inducing over-activation of the JAK/STAT pathway, and that the cytoplasmic JAK tyrosine kinases may also have a nuclear role. A couple of anti-JAK therapeutics have been developed, which effectively harness lymphoid cancer cells. Here we discuss mutations and fusions leading to JAK deregulations, how upstream nodes drive JAK expression, how classical JAK/STAT pathways are represented in lymphoid malignancies and the noncanonical and nuclear role of JAKs. We also summarize JAK inhibition therapeutics applied alone or synergized with other drugs in treating lymphoid malignancies.

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A novel model of alternative NF-κB pathway activation in anaplastic large cell lymphoma

Cited by 18 publications

References 44 publications

Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells

Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells

FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T cell lymphoma, not otherwise specified

Janus Kinase Signaling: Oncogenic Criminal of Lymphoid Cancers

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