MiR-16 regulates crosstalk in NF-κB tolerogenic inflammatory signaling between myeloma cells and bone marrow macrophages

Khalife, Jihane; Ghose, Jayeeta; Martella, Marianna; Viola, Domenico; Rocci, Alberto; Troadec, Estelle; Terrazas, César; Satoskar, Abhay R.; Gunes, Emine Gulsen; Donà, Ada; Sanchez, James F.; Bergsagel, P. Leif; Chesi, Marta; Pozhitkov, Alex; Rosen, Steven T.; Marcucci, Guido; Hofmeister, Craig C.; Krishnan, Amrita; Caserta, Enrico; Pichiorri, Flavia

doi:10.1172/jci.insight.129348

Cited by 38 publications

(37 citation statements)

References 57 publications

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“…Because we were not able to evaluate conditional Mir15a/Mir16-1 deletion in Vk*MYC mice, we wondered whether reduced Mir15a/ Mir16-1 expression in the multiple myeloma microenvironment could contribute to the phenotype we observed. Specifically, it has been reported that multiple myeloma cell lines cocultured with BM mesenchymal cells derived from MIR null , but not WT mice, display higher proliferation rates (22) and that Mir16 levels regulate the polarization state of tumor-promoting M2 macrophages (23,24). We therefore compared engraftment rate in WT, MDR het , and MDR null littermate recipient mice transplanted with Vk12598 multiple myeloma tumors lacking del (14), and found no differences in the time of appearance of M-spikes and their progression over time among the three cohorts analyzed ( Supplementary Fig.…”

Section: Monoallelic Loss Of Mir15a/mir16-1 Accelerates Myeloma Progrmentioning

confidence: 99%

Monosomic Loss of MIR15A/MIR16-1 Is a Driver of Multiple Myeloma Proliferation and Disease Progression

Chesi

Stein

Garbitt

et al. 2020

Blood Cancer Discovery

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The most common genetic abnormality in multiple myeloma is the deletion of chromosome 13, seen in almost half of newly diagnosed patients. Unlike chronic lymphocytic leukemia, where a recurrent minimally deleted region including MIR15A/MIR16-1 has been mapped, the deletions in multiple myeloma predominantly involve the entire chromosome and no specifi c driver gene has been identifi ed. Additional candidate loci include RB1 and DIS3 , but while biallelic deletion of RB1 is associated with disease progression, DIS3 is a common essential gene and complete inactivation is not observed. The Vk*MYC transgenic mouse model of multiple myeloma spontaneously acquires del(14), syntenic to human chromosome 13, and Rb1 complete inactivation, but not Dis3 mutations. Taking advantage of this model, we explored the role in multiple myeloma initiation and progression of two candidate loci on chromosome 13: RB1 and MIR15A/MIR16-1. Monoallelic deletion of Mir15a/Mir16-1, but not Rb1, was suffi cient to accelerate the development of monoclonal gammopathy in wild-type mice and the progression of multiple myeloma in Vk*MYC mice, resulting in increased expression of Mir15a/Mir16-1 target genes and plasma cell proliferation, which was similarly observed in patients with multiple myeloma. SIGNIFICANCE: In the absence of a defi ned, minimally deleted region the signifi cance of del(13) in multiple myeloma has remained controversial. Here we show that haploinsuffi ciency of Mir15a/Mir16-1 , but not Rb1 , upregulates the cell cycle-regulatory network, inducing monoclonal gammopathy in mice and promoting multiple myeloma progression in both mice and men.

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Section: Monoallelic Loss Of Mir15a/mir16-1 Accelerates Myeloma Progrmentioning

confidence: 99%

Monosomic Loss of MIR15A/MIR16-1 Is a Driver of Multiple Myeloma Proliferation and Disease Progression

Chesi

Stein

Garbitt

et al. 2020

Blood Cancer Discovery

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“… 28 In addition, the MEK/ERK pathway cascade is associated with RAS/RAF mutations, further driving mutation-inducing MM, and the activation of NF-κB is critical in supporting MM cell growth as well as in the formation of drug resistance. 19 , 29 Therefore, we speculated that PKD1 might be upregulated and associated with clinical characteristics in patients with MM, while the related evidence is lacking. First, we found that PKD1 mRNA and protein expressions were both increased in patients with MM compared with HCs and presented good value in distinguishing patients with MM from HCs.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase D 1 Predicts Poor Treatment Response and Unfavorable Survival of Bortezomib-Based Treatment, and Its Knockdown Enhances Drug Sensitivity to Bortezomib in Multiple Myeloma

2020

Technol Cancer Res Treat

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Objective: The present study aimed to explore the correlation of protein kinase D 1 with prognosis in bortezomib-treated multiple myeloma patients and further investigate the effect of protein kinase D 1 knockdown on drug sensitivity to bortezomib in multiple myeloma cells. Methods: Totally, 104 de novo symptomatic multiple myeloma patients treated with bortezomib-based regimens and 30 healthy controls were recruited. Bone marrow mononuclear cells–derived plasma cells were collected from multiple myeloma patients before initial treatment and from healthy controls on the bone marrow donation, respectively, then protein kinase D 1 protein/messenger RNA expressions were detected by Western blot and reverse transcription quantitative polymerase chain reaction, respectively. The effect of protein kinase D 1 knockdown on drug sensitivity to bortezomib was detected by transfecting protein kinase D 1 knockdown plasmid and control plasmid into RPMI8226 and U266 cells. Results: Protein kinase D 1 protein/messenger RNA expressions were both upregulated in multiple myeloma patients compared with healthy controls and presented good value in differentiating multiple myeloma patients from healthy controls. Furthermore, protein kinase D 1 protein/messenger RNA expressions were both associated with high International Staging System stage and t (4; 14). Furthermore, both complete response rate and overall response rate were reduced in protein kinase D 1 high patients compared with protein kinase D 1 low patients; similarly, progression-free survival and overall survival were both decreased in protein kinase D 1 high patients compared with protein kinase D 1 low patients. In addition, in RPMI8226 and U266 multiple myeloma cells, protein kinase D 1 knockdown increased drug sensitivity to bortezomib. Conclusion: Protein kinase D 1 has the potential to predict poor treatment response and unfavorable survival of bortezomib-based treatment in multiple myeloma patients, and its knockdown enhanced drug sensitivity to bortezomib in multiple myeloma cells.

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“…However, EVs isolated from PCs without the chromosomal aberration did not affect monocyte differentiation. Mechanistically, we showed that miR- 16 directly targeted and inhibited the IKKα/β complex of the NF-κB canonical pathway, which is critical not only in supporting MM cell growth, but also in polarizing macrophages toward an M2 tumor-supportive phenotype [ 67 ].…”

Section: Extracellular Vesicles: Biogenesis Composition and Cellmentioning

confidence: 99%

“…Because culture media is considered a relatively simple chemical composition devoid of protein or sugar contaminants, EV purity is not an issue in this case. We have routinely used ultrafiltration as a method of EV extraction from cultured MM cells for biomarker detection or functional analysis [ 67 , 76 ]. Although isolation of urinary EVs using a nanomembrane ultrafiltration concentrator has been shown to yield a high purity index suitable for the analysis of exosomal biomarkers [ 123 ], ultrafiltration is not the primary method applied to isolate EVs from plasma or serum because of significant losses due to unspecific membrane adsorption and the limited amount of blood available from cancer patients to use for liquid biopsy.…”

Section: Isolation and Characterization Of Evs For Liquid Biopsymentioning

confidence: 99%

Extracellular Vesicles in Hematological Malignancies: From Biomarkers to Therapeutic Tools

2020

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Small extracellular vesicles (EVs) are a heterogenous group of lipid particles released by all cell types in physiological and pathological states. In hematological malignancies, tumor-derived EVs are critical players in mediating intercellular communications through the transfer of genetic materials and proteins between neoplastic cells themselves and to several components of the bone marrow microenvironment, rendering the latter a “stronger” niche supporting cancer cell proliferation, drug resistance, and escape from immune surveillance. In this context, the molecular cargoes of tumor-derived EVs reflect the nature and status of the cells of origin, making them specific therapeutic targets. Another important characteristic of EVs in hematological malignancies is their use as a potential “liquid biopsy” because of their high abundance in biofluids and their ability to protect their molecular cargoes from nuclease and protease degradation. Liquid biopsies are non-invasive blood tests that provide a molecular profiling clinical tool as an alternative method of disease stratification, especially in cancer patients where solid biopsies have limited accessibility. They offer accurate diagnoses and identify specific biomarkers for monitoring of disease progression and response to treatment. In this review, we will focus on the role of EVs in the most prevalent hematological malignancies, particularly on their prospective use as biomarkers in the context of liquid biopsies, as well as their molecular signature that identifies them as specific therapeutic targets for inhibiting cancer progression. We will also highlight their roles in modulating the immune response by acting as both immunosuppressors and activators of anti-tumor immunity.

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MiR-16 regulates crosstalk in NF-κB tolerogenic inflammatory signaling between myeloma cells and bone marrow macrophages

Cited by 38 publications

References 57 publications

Monosomic Loss of MIR15A/MIR16-1 Is a Driver of Multiple Myeloma Proliferation and Disease Progression

Monosomic Loss of MIR15A/MIR16-1 Is a Driver of Multiple Myeloma Proliferation and Disease Progression

Protein Kinase D 1 Predicts Poor Treatment Response and Unfavorable Survival of Bortezomib-Based Treatment, and Its Knockdown Enhances Drug Sensitivity to Bortezomib in Multiple Myeloma

Extracellular Vesicles in Hematological Malignancies: From Biomarkers to Therapeutic Tools

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