Super enhancer-mediated upregulation of HJURP promotes growth and survival of t(4;14)-positive multiple myeloma

The Ikaros zing-finger family transcription factors (IKZF TFs) are important regulators of lymphocyte development and differentiation and are also highly expressed in B cell malignancies, including Multiple Myeloma (MM), where they are required for cancer cell growth and survival. Moreover, IKZF TFs negatively control the functional properties of many immune cells. Thus, the targeting of these proteins has relevant therapeutic implications in cancer. Indeed, accumulating evidence demonstrated that downregulation of Ikaros and Aiolos, two members of the IKZF family, in malignant plasma cells as well as in adaptative and innate lymphocytes, is key for the anti-myeloma activity of Immunomodulatory drugs (IMiDs). This review is focused on IKZF TF-related pathways in MM. In particular, we will address how the depletion of IKZF TFs exerts cytotoxic effects on MM cells, by reducing their survival and proliferation, and concomitantly potentiates the antitumor immune response, thus contributing to therapeutic efficacy of IMiDs, a cornerstone in the treatment of this neoplasia.

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The effects on growth and survival of IL‐6 can be dissociated in the U‐266‐1970/U‐266‐1984 and HL407E/HL407L human multiple myeloma cell lines

British Journal of Haematology ◽

10.1046/j.1365-2141.1997.1903004.x ◽

1997 ◽

Vol 98 (1) ◽

pp. 126-133 ◽

Cited By ~ 14

Author(s):

Helena Spets ◽

Helena Jernberg‐Wiklund ◽

Clara Sambade ◽

Ola Söderberg ◽

Kenneth Nilsson

Keyword(s):

Multiple Myeloma ◽

Cell Lines ◽

Myeloma Cell ◽

Growth And Survival ◽

Multiple Myeloma Cell ◽

Human Multiple Myeloma

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P-099: Perturbation of CDK7 and super-enhancer driven transcriptional programs synergistically halts multiple myeloma cell proliferation

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/s2152-2650(21)02233-3 ◽

2021 ◽

Vol 21 ◽

pp. S93

Author(s):

Yao Yao ◽

Woojun D Park ◽

Eugenio Morelli ◽

Mehmet K Samur ◽

Nicholas Kwiatkowski ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Proliferation ◽

Myeloma Cell ◽

Multiple Myeloma Cell ◽

Super Enhancer

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KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival

Leukemia ◽

10.1038/leu.2017.141 ◽

2017 ◽

Vol 31 (12) ◽

pp. 2661-2669 ◽

Cited By ~ 27

Author(s):

H Ohguchi ◽

T Harada ◽

M Sagawa ◽

S Kikuchi ◽

Y-T Tai ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Growth ◽

Mapk Pathway ◽

Myeloma Cell ◽

Growth And Survival ◽

Multiple Myeloma Cell ◽

Cell Growth And Survival

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IL-32 is a metabolic regulator promoting survival and proliferation of malignant plasma cells

10.1101/2021.02.22.431638 ◽

2021 ◽

Author(s):

Kristin Roseth Aass ◽

Robin Mjelle ◽

Martin H. Kastnes ◽

Synne S. Tryggestad ◽

Luca M. van den Brink ◽

...

Keyword(s):

Multiple Myeloma ◽

Oxidative Phosphorylation ◽

Plasma Cells ◽

Inflammatory Diseases ◽

Mitochondrial Respiratory Chain ◽

Gene Signature ◽

Growth And Survival ◽

Novel Concept

AbstractIL-32 is a non-classical cytokine expressed in cancers, inflammatory diseases and infections. IL-32 can have both extracellular and intracellular functions, and its receptor is not identified. We here demonstrate that endogenously expressed, intracellular IL-32 binds to components of the mitochondrial respiratory chain and promotes oxidative phosphorylation. Knocking out IL-32 in malignant plasma cells significantly reduced survival and proliferation in vitro and in vivo. High throughput transcriptomic and MS-metabolomic profiling of IL-32 KO cells revealed that loss of IL-32 leads to profound perturbations in metabolic pathways, with accumulation of lipids, pyruvate precursors and citrate, indicative of reduced mitochondrial function. IL-32 is expressed in a subgroup of multiple myeloma patients with an inferior prognosis. Primary myeloma cells expressing IL-32 were characterized by a plasma cell gene signature associated with immune activation, proliferation and oxidative phosphorylation. We propose a novel concept for regulation of metabolism by an intracellular cytokine and identify IL-32 as an endogenous growth and survival factor for malignant plasma cells. IL-32 is a potential prognostic biomarker and a treatment target in multiple myeloma.

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MIP-1α (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma

Blood ◽

10.1182/blood-2006-04-017087 ◽

2006 ◽

Vol 108 (10) ◽

pp. 3465-3471 ◽

Cited By ~ 54

Author(s):

Esther Masih-Khan ◽

Suzanne Trudel ◽

Carla Heise ◽

Zhihua Li ◽

Joshua Paterson ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Bone Disease ◽

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Transcriptional Response ◽

Mapk Signaling ◽

Growth And Survival ◽

Ras Mutations ◽

Downstream Target

Abstract Overexpression of fibroblast growth factor receptor 3 (FGFR3) is a hallmark of t(4;14) multiple myeloma (MM). To dissect the mechanism of FGFR3 oncogenesis in MM, we used 3 FGFR selective kinase inhibitors—CHIR258, PD173074, and SU5402—and FGFR3-specific siRNA to modulate FGFR3 activity. Conversely, the ligand FGF was used to stimulate FGFR3 function in human MM cells. The transcriptional response to FGFR3 modification was recorded, and gene expression changes common to all 5 modifiers were documented. Ten genes were commonly regulated. Macrophage inflammatory protein-1 alpha (MIP-1α) was the single most differentially altered gene. MIP-1 α promoter function, gene expression, and protein secretion were each down-regulated following inhibition of FGFR3 signaling. Down-regulation of MIP-1 α was not, however, observed following FGFR3 inhibition in MM cells with RAS mutations implicating RAS-MAPK in MIP-1 α regulation. As confirmation, inhibition of ERK1 also down-regulated MIP-1 α in FGFR3 inhibitor-resistant cells harboring RAS mutations. MIP-1 α is implicated in the survival and proliferation of MM cells and the pathogenesis of MM bone disease. Our observation is the first to directly link an initiating IgH translocation not only to MM-cell growth and survival but also to the disease-associated bone disease.

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Biologic sequelae of IκB kinase (IKK) inhibition in multiple myeloma: therapeutic implications

Blood ◽

10.1182/blood-2008-06-161505 ◽

2009 ◽

Vol 113 (21) ◽

pp. 5228-5236 ◽

Cited By ~ 57

Author(s):

Teru Hideshima ◽

Dharminder Chauhan ◽

Tanyel Kiziltepe ◽

Hiroshi Ikeda ◽

Yutaka Okawa ◽

...

Keyword(s):

Multiple Myeloma ◽

Growth Inhibition ◽

Cell Lines ◽

Nuclear Factor Κb ◽

Down Regulation ◽

Growth And Survival ◽

Therapeutic Implications ◽

Iκb Kinase ◽

Canonical Pathways ◽

Promising Treatment

Abstract Nuclear factor-κB (NF-κB) has an important role in multiple myeloma (MM) cell pathogenesis in the context of the bone marrow (BM) microenvironment. In NF-κB signaling cascades, IκB kinase α (IKKα) and IKKβ are key molecules that predominantly mediate noncanonical and canonical pathways, respectively. In this study, we examined the biologic sequelae of the inhibition of IKKα versus IKKβ in MM cell lines. All MM cell lines have constitutive canonical NF-κB activity, and a subset of MM cell lines shows noncanonical NF-κB activity. Adhesion to BM stromal cells further activates both canonical and noncanonical NF-κB activity. IKKβ inhibitor MLN120B blocks canonical pathway and growth of MM cell lines but does not inhibit the noncanonical NF-κB pathway. Although IKKα knockdown induces significant growth inhibition in the cell lines with both canonical and noncanonical pathways, it does not inhibit NF-κB activation. Importantly, IKKα down-regulation decreases expression of β-catenin and aurora-A, which are known to mediate MM cell growth and survival. Finally, IKKβ inhibitor enhances the growth inhibition triggered by IKKα down-regulation in MM cells with both canonical and noncanonical NF-κB activity. Combination therapy targeting these kinases therefore represents a promising treatment strategy in MM.

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