Co-culture of primary CLL cells with bone marrow mesenchymal cells, CD40 ligand and CpG ODN promotes proliferation of chemoresistant CLL cells phenotypically comparable to those proliferating<i>in vivo</i>

Purroy, Noelia; Abrisqueta, Pau; Carabia, Júlia; Carpio, Cecilia; Palacio, Carles; Bosch, Francesc; Crespo, Marta

doi:10.18632/oncotarget.2939

Cited by 43 publications

(47 citation statements)

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“…Because resistance was greatest in cells expressing the activation marker CD69, characteristic of LN resident cells, we hypothesized that cellular activation by microenvironmental interactions could generate this ex vivo resistance (Fig. S7), which was also suggested by recent studies 26–32 .…”

Section: 0 Discussionmentioning

confidence: 75%

“…S7), and hypothesized that extrinsic microenvironmental factors, which are capable of activating B-cells 26–29,33–40 , might induce drug resistance. To test this, three representative CLL patient PBMCs were pre-incubated with soluble CD40L (sCD40L), CXCL13, IL-10, IL-2, CpG-ODN, BAFF, or IgM; or co-cultured with a Follicular Dendritic Cell line (HK) or a Bone Marrow Stromal Cell line (HS-5) 26–29,33–40 and treated with IBR+VEN as described in Fig. 2A.…”

Section: 0 Resultsmentioning

confidence: 99%

“…Interaction of CLL/MCL cells with microenvironmental agonists can induce B-cell activation 16,42 , and drug resistance 26–32 . Therefore, we tested the ability of various cells and agonists that are expected to be found in the cancer cell environment 26–29,33–40 to protect leukemic cells from cytotoxicity of IBR+VEN.…”

Section: 0 Discussionmentioning

confidence: 99%

“…Therefore, we tested the ability of various cells and agonists that are expected to be found in the cancer cell environment 26–29,33–40 to protect leukemic cells from cytotoxicity of IBR+VEN. Pre-treatment of CLL patient PBMCs with several of these agonists was protective (Figs.…”

Section: 0 Discussionmentioning

confidence: 99%

“…Although this variability could reflect genetic heterogeneity in these patients 25 , we hypothesized that the de novo resistance could also be generated by variability in the in vivo environment of cancer cells 26–32 . Neoplastic B cells receive growth/survival signals through interaction with components of the microenvironment such as stromal cells, cytokines, antigens, and circulating microbial/cellular DNA 16,26–29,33–42 ; the latter three are found in lymph node (LN) and bone marrow (BM) as well as in circulation.…”

Section: 0 Introductionmentioning

confidence: 99%

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Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL

Jayappa

Portell²,

Gordon

et al. 2017

Blood Advances

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De novo resistance and rapid recurrence often characterize responses of B-cell malignancies to ibrutinib (IBR), indicating a need to develop drug combinations that block compensatory survival signaling and give deeper, more durable responses. To identify such combinations, we previously performed a combinatorial drug screen and identified the Bcl-2 inhibitor venetoclax (VEN) as a promising partner for combination with IBR in Mantle Cell Lymphoma (MCL). We have opened a multi-institutional clinical trial to test this combination. However, analysis of primary samples from patients with MCL as well as chronic lymphocytic leukemia (CLL) revealed unexpected heterogeneous de novo resistance even to the IBR+VEN combination. In the current study, we demonstrate that resistance to the combination can be generated by microenvironmental agonists: IL-10, CD40L and, most potently, CpG-oligodeoxynucleotides (CpG-ODN), which is a surrogate for unmethylated DNA and a specific agonist for TLR9 signaling. Incubation with these agonists caused robust activation of NF-κB signaling, especially alternative NF-κB, which led to enhanced expression of the anti-apoptotic proteins Mcl-1, Bcl-xL, and survivin, thus decreasing dependence on Bcl-2. Inhibitors of NF-κB signaling blocked overexpression of these anti-apoptotic proteins and overcame resistance. Inhibitors of Mcl-1, Bcl-xL, or survivin also overcame this resistance, and showed synergistic benefit with the IBR+VEN combination. We conclude that microenvironmental factors, particularly the TLR9 agonist, can generate de novo resistance to the IBR+VEN combination in CLL and MCL cells. This signaling pathway presents targets for overcoming drug resistance induced by extrinsic microenvironmental factors in diverse B-cell malignancies.

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Section: 0 Discussionmentioning

confidence: 75%

Section: 0 Resultsmentioning

confidence: 99%

Section: 0 Discussionmentioning

confidence: 99%

Section: 0 Discussionmentioning

confidence: 99%

Section: 0 Introductionmentioning

confidence: 99%

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Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL

Jayappa

Portell²,

Gordon

et al. 2017

Blood Advances

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DAPK3 participates in the mRNA processing of immediate early genes in chronic lymphocytic leukaemia

et al. 2020

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Cross-linking of the B-cell receptor (BCR) induces transcriptional activation of immediate early genes (IEGs) including EGR1 and DUSP2 in chronic lymphocytic leukaemia (CLL). Here, we have shown that this transcriptional activation correlated with histone H3 threonine 6 and 11 phosphorylation.Both transcription and histone post-translational modifications are repressed by ibrutinib, a small molecule inhibitor used in CLL treatment. Moreover, we have identified the death-associated protein kinase 3 (DAPK3), as the kinase mediating these histone phosphorylation marks in response to activation of the BCR signalling pathway with this kinase being recruited to RNA polymerase II in an anti-IgM-dependent manner. DAPK inhibition mimics ibrutinib-induced repression of both IEG mRNA and histone H3 phosphorylation and has anti-proliferative effect comparable to ibrutinib in CLL in vitro. DAPK inhibitor does not repress transcription itself but impacts on mRNA processing and has a broader anti-tumour effect than ibrutinib, by repressing both anti-IgMand CD40L-dependent activation.Abbreviations (U/M)-CLL, (unmutated/mutated)-chronic lymphocytic leukaemia; BCR, B-cell receptor; BTK, Bruton's tyrosine kinase; Co-IP, coimmunoprecipitation; CpG ODN, CpG oligodeoxynucleotides; DAPK1, death-associated protein kinase 1; DAPK3, death-associated protein kinase 3; DAPKi, DAPK inhibitor; DLBCL, diffuse large B-cell lymphoma; DUSP2, dual-specificity phosphatase 2; EGR1, early growth response 1; GAIT, interferon-gamma-activated inhibitor of translation; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; H3T11-P, histone H3 threonine 11 phosphorylation; H3T6-P, histone H3 threonine 6 phosphorylation; IEG, immediate early gene; IFNc, interferongamma; IgHV, immunoglobulin heavy chain variable (region); Kb, kilobase; MYD88, myeloid differentiation primary response 88; NF-jB, nuclear factor-kappa B; NLC, nurse-like cell; PLCc2, phospholipase Cc2; PPP6C, protein phosphatase 6 catalytic subunit; PTM, posttranslational modification; qPCR, quantitative polymerase chain reaction; RNA pol II S2-P, RNA polymerase II serine 2 phosphorylation; RPMI, Roswell Park Memorial Institute (media); siRNA, small interfering ribonucleic acid; TBP, TATA-box binding protein; TLR, Toll-like receptor; TSS, transcription start site; ZIPK, zipper-interacting protein kinase.

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Mechanisms of Resistance to Targeted Therapies in Chronic Lymphocytic Leukemia

Arruga

Deaglio

2017

Handbook of Experimental Pharmacology

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Even if treatment options for Chronic Lymphocytic Leukemia (CLL) patients have changed dramatically in the past few years, with the approval of targeted therapeutic agents, the disease remains incurable. Beside intrinsic genetic features characterizing the leukemic cell, signals coming from the microenvironment have a key role in promoting cell survival and in protecting CLL cells from the action of drugs. Consequently, the identification of previously unrecognized genetic lesions is important in risk-stratification of CLL patients and is progressively becoming a critical tool for choosing the best therapeutic strategy. Significant efforts have also been dedicated to define microenvironment-dependent mechanisms that sustain leukemic cells favoring survival, proliferation, and accumulation of additional genetic lesions. Furthermore, understanding the molecular and biological mechanisms, potentially driving disease progression and chemoresistance, is the first step to design therapies that could be effective in high-risk patients. Significant progress has been made in the identification of the different mechanisms through which patients relapse after "new" and "old" therapies. These studies have led to the development of targeted strategies to overcome, or even prevent, resistance through the design of novel agents or their combination.In this chapter we will give an overview of the main therapeutic options for CLL patients and review the mechanisms of resistance responsible for treatment failure. Potential strategies to overcome or prevent resistance will be also discussed.

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Co-culture of primary CLL cells with bone marrow mesenchymal cells, CD40 ligand and CpG ODN promotes proliferation of chemoresistant CLL cells phenotypically comparable to those proliferatingin vivo

Cited by 43 publications

References 45 publications

Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL

Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL

DAPK3 participates in the mRNA processing of immediate early genes in chronic lymphocytic leukaemia

Mechanisms of Resistance to Targeted Therapies in Chronic Lymphocytic Leukemia

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