Expression data from 3 gamma-secretase or mock-treated mantle cell lymphoma (MCL) cell lines
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Robert Kridel
PROVIDER: E-GEOD-34602 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:We identified recurrent NOTCH1 mutations in 12% of MCLs. 2 out of 10 tested MCL cell lines (Rec-1 and SP-49) were sensitive to inhibition of the NOTCH pathway by gamma-secretase inhibition. The aim of this study was to identify transcriptional targets of NOTCH signaling in MCL.
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Project description:Poor prognosis BCR-ABL+ B-ALL leukemic cells are highly dependent on the expression of endogenous anti-apoptotic MCL-1. However, the survival of most normal blood cells (e.g. progenitors, lymphocytes, and granulocytes) and other normal cell types (e.g. cardiomyocytes and neurons) are also exquisitely dependent on Mcl-1 gene expression, suggesting that effective therapeutic inhibition of MCL-1 could be acutely toxic, especially when combined with standard chemotherapy. Therefore, as an alternative to MCL-1 inhibition, we have identified dihydroarteminisin (DHA), a water-soluble metabolite of the anti-malarial arteminisin, which induces the down-modulation of MCL-1 protein expression by triggering an endoplasmic reticulum stress response. The DHA induced repression of MCL-1 expression renders leukemic cells highly sensitive to synergistic cell death induced by BH3-mimetic agents such as navitoclax (ABT-263) in a mouse model of BCR-ABL+ B-ALL. Furthermore, DHA also synergizes with navitoclax in human Ph+ ALL cell lines, and primary patient derived xenografts of Ph+ ALL. These data demonstrate that combining DHA with BH3-mimetic agents can improve therapeutic response in poor prognosis leukemia.
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Project description:Manuscript Title:
Co-targeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma
Journal:
Journal of Clinical Investigation
Authors
Vivian Changying Jiang1, Yang Liu1, Junwei Lian1, Shengjian Huang1, Alexa Jordan1, Qingsong Cai1, Fangfang Yan3, Joseph Mitchell McIntosh1, Yijing Li1, Yuxuan Che1, Zhihong Chen1, Jovanny Vargas1, Maria Badillo1, JohnNelson Bigcal1, Heng-Huan Lee1, Wei Wang1, Yixin Yao1, Lei Nie1, Christopher Flowers1, and Michael Wang1, 2*
Abstract
Bruton’s tyrosine kinase (BTK) is a proven target in mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma. However, resistance to BTK inhibitors is a major clinical challenge. We here report that MALT1 is one of the top overexpressed genes in ibrutinib-resistant MCL cells, while expression of CARD11, which is upstream of MALT1, is decreased. MALT1 genetic knockout or inhibition produced dramatic defects in MCL cell growth regardless of ibrutinib sensitivity. Conversely, CARD11 knockout cells showed anti-tumor effects only in ibrutinib-sensitive cells, suggesting that MALT1 overexpression could drive ibrutinib resistance via bypassing BTK-CARD11 signaling. Additionally, BTK knockdown and MALT1 knockout markedly impaired MCL tumor migration and dissemination, and MALT1 pharmacological inhibition decreased MCL cell viability, adhesion, and migration by suppressing NF-κB, PI3K-ATK-mTOR, and integrin signaling. Importantly, co-targeting MALT1 with safimaltib and BTK with pirtobrutinib induced potent anti-MCL activity in ibrutinib-resistant MCL cell lines and patient-derived xenografts. Therefore, we conclude that MALT1 overexpression associates with resistance to BTK inhibitors in MCL, targeting abnormal MALT1 activity could be a promising therapeutic strategy to overcome BTK inhibitor resistance, and co-targeting of MALT1 and BTK should improve MCL treatment efficacy and durability as well as patient outcomes.
Dataset description:
The bulk RNA-seq dataset was generated for the cell lines below and used for two major purposes:
1. DEG analysis and GSEA analysis comparing IBN-R and IBN-S cells
2. DEG analysis and GSEA analysis comparing MCL cells with/without MI-2 treatment.
sample Cell MI-2 Ibrutinib (IBN) Venetoclax (VEN) Used for IBN-R vs IBN-S comparison Used for MI-2 vs untreated (DMSO)
H9 Granta519 - R S yes
H21 Granta519 - R S yes
H33 Granta519 - R S yes
H10 Granta519-VEN-R - R R yes
H22 Granta519-VEN-R - R R yes
H34 Granta519-VEN-R - R R yes
H3 JeKo BTK KD_1 - R R yes yes
H15 JeKo BTK KD_1 - R R yes yes
H27 JeKo BTK KD_1 - R R yes yes
H5 JeKo BTK KD_2 - R R yes yes
H17 JeKo BTK KD_2 - R R yes yes
H29 JeKo BTK KD_2 - R R yes yes
H1 JeKo-1 - S R yes yes
H13 JeKo-1 - S R yes yes
H25 JeKo-1 - S R yes yes
H7 Mino - S S yes
H19 Mino - S S yes
H31 Mino - S S yes
H8 Mino-VEN-R - S R yes
H20 Mino-VEN-R - S R yes
H32 Mino-VEN-R - S R yes
H11 Rec-1 - S S yes
H23 Rec-1 - S S yes
H12 Rec-VEN-R - S S yes
H24 Rec-VEN-R - S R yes
H36 Rec-VEN-R - S R yes
H35 Rec-1 -- S R yes
H4 JeKo BTK KD_1 + MI-2 + yes
H16 JeKo BTK KD_1 + MI-2 + yes
H28 JeKo BTK KD_1 + MI-2 + yes
H6 JeKo BTK KD_2 + MI-2 + yes
H18 JeKo BTK KD_2 + MI-2 + yes
H30 JeKo BTK KD_2 + MI-2 + yes
H2 JeKo-1 + MI-2 + yes
H14 JeKo-1 + MI-2 + yes
H26 JeKo-1 + MI-2 + yes
| EGAD00001009771 | EGA
Project description:Mantle cell lymphoma (MCL) is an aggressive B-cell non-HodgkinM-bM-^@M-^Ys lymphoma (NHL). In cancers, tumour suppressive microRNAs may be silenced by DNA hypermethylation. By microRNA profiling, miR-155-3p was significantly upregulated upon demethylation treatment of MCL cell lines with 5-aza-2M-bM-^@M-^Y-deoxycytidine (5-azadC). Methylation-specific PCR, verified by pyrosequencing, showed complete methylation of miR-155-3p in one MCL cell line (REC-1). 5-azadC treatment of REC-1 led to demethylation and re-expression of miR-155-3p. Over-expression of miR-155-3p led to increased sub-G1 apoptotic cells and reduced cellular viability, demonstrating its tumour suppressive properties. By luciferase assay, lymphotoxin-beta (LT-M-NM-2) was validated as a miR-155-3p target. In 31 primary MCL, miR-155-3p was found hypermethylated in 6(19%) cases. To test if methylation of miR-155-3p was MCL-specific, miR-155-3p methylation was tested in an additional 191 B-cell, T-cell and NK-cell NHLs, yielding miR-155-3p methylation in 66(34.6%) including 36(27%) non-MCL B-cell, 24(53%) T-cell and 6(46%) of NK-cell lymphoma. Moreover, in 72 primary NHL samples with RNA, miR-155-3p methylation correlated with miR-155-3p downregulation (p=0.030), and LT-M-NM-2 upregulation (p=0.004). Collectively, miR-155-3p is tumour suppressive microRNA hypermethylated in MCL and other NHL subtypes. As miR-155-3p targets LT-M-NM-2, which is an upstream activator of the non-canonical NF-kB signalling, miR-155-3p methylation is potentially important in lymphomagenesis Total RNA isolated from MINO and JEKO-1 before and after 5-azadC treatment were converted into cDNA by MegaplexTM RT Primers and TaqManM-BM-. MicroRNA Reverse Transcription Kit. cDNA was pre-amplified using MegaplexTM PreAmp Primer and loaded onto 384-well format TaqmanM-BM-. human microRNA array A V2.0 & B V3.0. Real-time PCR was performed on 7900HT Real-Time PCR system and raw data were analyzed normalizing to mean of three endogenous controls (U6snRNA, RNU44 and RNU48). Relative microRNA levels were determined by M-NM-^TM-NM-^TCt using endogenous controls and untreated controls using SDS 2.4 and RQ manager 1.2. All experimental procedures and analyses were performed according to manufacturerM-bM-^@M-^Ys instruction, using reagents, system and softwares acquired from Applied Biosystems (Foster City, USA).
2014-08-31 | E-GEOD-57128 | biostudies-arrayexpress
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2013-12-14 | E-GEOD-53309 | biostudies-arrayexpress
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| PRJNA176358 | ENA