Targeting MYC activity in double-hit lymphoma with MYC and BCL2 and/or BCL6 rearrangements with epigenetic bromodomain inhibitors

Li, Weiping; Gupta, Shiv K.; Han, Weiguo; Kundson, Ryan A.; Nelson, Sara; Knutson, Darlene L.; Greipp, Patricia T.; Elsawa, Sherine F.; Sotomayor, Eduardo M.; Gupta, Mamta

doi:10.1186/s13045-019-0761-2

Cited by 78 publications

(63 citation statements)

References 43 publications

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“…Even in cell lines with comparatively lower PNDD1 uptake, such as OCI-Ly3, the induction of cell death was robust. It might be because these cells are highly dependent on Myc activity, as a study has recently shown that OCI-LY3 contains multiple copies of MYC 38 . By contrast, the immortalised normal B-cells were able to stop proliferation without significant cell death.…”

Section: Discussionmentioning

confidence: 99%

Targeting c-Myc with a novel Peptide Nuclear Delivery Device

Ting

Chaumet

Bard

2020

Sci Rep

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Biologics such as peptides and antibodies are a well-established class of therapeutics. However, their intracellular delivery remains problematic. In particular, methods to efficiently inhibit intra-nuclear targets are lacking. We previously described that Pseudomonas Exotoxin A reaches the nucleoplasm via the endosomes-to-nucleus trafficking pathway. Here, we show that a non-toxic truncated form of PE can be coupled to peptides and efficiently reach the nucleoplasm. It can be used as a Peptide Nuclear Delivery Device (PNDD) to deliver polypeptidic cargos as large as Glutathione- S-transferase (GST) to the nucleus. PNDD1 is a fusion of PNDD to the c-myc inhibitor peptide H1. PNDD1 is able to inhibit c-Myc dependent transcription at nanomolar concentration. In contrast, H1 fused to various cell-penetrating peptides are active only in the micromolar range. PNDD1 attenuates cell proliferation and induces cell death in various tumor cell lines. In particular, several patient-derived Diffuse Large B-Cell Lymphomas cell lines die after exposure to PNDD1, while normal B-cells survive. Altogether, our data indicate that PNDD is a powerful tool to bring active cargo to the nucleus and PNDD1 could be the basis of a new therapy against lymphoma.

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Section: Discussionmentioning

confidence: 99%

Targeting c-Myc with a novel Peptide Nuclear Delivery Device

Ting

Chaumet

Bard

2020

Sci Rep

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“…Furthermore, two other cohorts of de novo and relapsed DLBCL patients reported a negative correlation between MYC and PD-L1 [ 63 , 64 ]. Finally, some other studies were not able to detect any correlation between MYC and PD-L1 at all in either DLBCL cell lines [ 80 ], nor in DLBCL patients [ 60 , 66 , 68 , 81 ]. Notably, EBV infection causes B cells to escape from immune surveillance [ 82 , 83 ] partly by PD-L1 overexpression [ 84 , 85 ], adding further complexity to the relationship between MYC and PD-L1 in EBV-associated DLBCL and BL.…”

Section: The Role Of Myc Overexpression On the Immune System In Lymentioning

confidence: 95%

“…In addition to its different effects on NK cells, MYC was found to impair innate immunity by its effects on tumor-associated macrophages (TAMs). In a mouse model of T-ALL overexpressing Myc and in DLBCL cell lines, Myc was associated with high CD47 expression on tumor cells, suppressing recruitment of macrophages and tumor phagocytosis [ 75 , 80 ]. Moreover, inactivation of Myc increased activation of innate immune cells and recruitment of macrophages to the tumor microenvironment [ 90 ].…”

Section: The Role Of Myc Overexpression On the Immune System In Lymentioning

confidence: 99%

“…JQ1 is a small molecule that competitively binds to BRD4 [ 130 ]. JQ1 is widely used to study the effects of MYC downregulation in lymphoid malignancies [ 75 , 76 , 80 , 131 ]. Bromodomain inhibitor analog, CPI-0610, has been well tolerated in patients with DLBCL in a phase I study [ 132 ].…”

Section: Direct and Indirect Myc Modulating Drugs And Consequencesmentioning

confidence: 99%

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Impact of MYC on Anti-Tumor Immune Responses in Aggressive B Cell Non-Hodgkin Lymphomas: Consequences for Cancer Immunotherapy

Jonge

Mutis

Roemer

et al. 2020

Cancers

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Patients with MYC overexpressing high grade B cell lymphoma (HGBL) face significant dismal prognosis after treatment with standard immunochemotherapy regimens. Recent preclinical studies indicate that MYC not only contributes to tumorigenesis by its effects on cell proliferation and differentiation, but also plays an important role in promoting escape from anti-tumor immune responses. This is of specific interest, since reversing tumor immune inhibition with immunotherapy has shown promising results in the treatment of both solid tumors and hematological malignancies. In this review, we outline the current understanding of impaired immune responses in B cell lymphoid malignancies with MYC overexpression, with a particular emphasis on diffuse large B cell lymphoma. We also discuss clinical consequences of MYC overexpression in the treatment of HGBL with novel immunotherapeutic agents and potential future treatment strategies.

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“…However, in the SADAL trial [ 3 ], patients with MYC high (but not BCL2 high ) expression had a lower overall response rate than those without. MYC expression can be inhibited by targeting the bromodomain and extra-terminal domain (BET) proteins [ 12 ]. We therefore combined selinexor with a novel BET inhibitor INCB057643.…”

Section: To the Editormentioning

confidence: 99%

XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53

et al. 2020

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The XPO1 inhibitor selinexor was recently approved in relapsed/refractory DLBCL patients but only demonstrated modest anti-DLBCL efficacy, prompting us to investigate the prognostic effect of XPO1 in DLBCL patients and the rational combination therapies in high-risk DLBCL. High XPO1 expression (XPO1high) showed significant adverse prognostic impact in 544 studied DLBCL patients, especially in those with BCL2 overexpression. Therapeutic study in 30 DLBCL cell lines with various molecular and genetic background found robust cytotoxicity of selinexor, especially in cells with BCL2-rearranged (BCL2-R+) DLBCL or high-grade B-cell lymphoma with MYC/BCL2 double-hit (HGBCL-DH). However, expression of mutant (Mut) p53 significantly reduced the cytotoxicity of selinexor in overall cell lines and the BCL2-R and HGBCL-DH subsets, consistent with the favorable impact of XPO1high observed in Mut-p53-expressing patients. The therapeutic effect of selinexor in HGBCL-DH cells was significantly enhanced when combined with a BET inhibitor INCB057643, overcoming the drug resistance in Mut-p53-expressing cells. Collectively, these data suggest that XPO1 worsens the survival of DLBCL patients with unfavorable prognostic factors such as BCL2 overexpression and double-hit, in line with the higher efficacy of selinexor demonstrated in BCL2-R+ DLBCL and HGBCL-DH cell lines. Expression of Mut-p53 confers resistance to selinexor treatment, which can be overcome by combined INCB057643 treatment in HGBCL-DH cells. This study provides insight into the XPO1 significance and selinexor efficacy in DLBCL, important for developing combination therapy for relapsed/refractory DLBCL and HGBCL-DH.

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Targeting MYC activity in double-hit lymphoma with MYC and BCL2 and/or BCL6 rearrangements with epigenetic bromodomain inhibitors

Cited by 78 publications

References 43 publications

Targeting c-Myc with a novel Peptide Nuclear Delivery Device

Targeting c-Myc with a novel Peptide Nuclear Delivery Device

Impact of MYC on Anti-Tumor Immune Responses in Aggressive B Cell Non-Hodgkin Lymphomas: Consequences for Cancer Immunotherapy

XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53

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