The miR‐15 family reinforces the transition from proliferation to differentiation in pre‐B cells

Lindner, Silke E.; Lohmüller, Michael; Kotkamp, Bianka; Schuler, Fabian; Knust, Z; Villunger, Andreas; Herzog, Sebastian

doi:10.15252/embr.201643735

Cited by 35 publications

(47 citation statements)

References 69 publications

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“…The MIR15A/MIR16-1 cluster is located within the CLL 13q14 MDR and it has been shown to directly regulate the expression of several cell cycle-controlling genes (CCND1-3, CDK4 and 6, CHK1, MCM5, and CDC25A). Consistently, loss of MIR15A/MIR16-1 drives B-cell expansion in vitro and in vivo by promoting G 0 -G 1 -S transition in both murine and human B cells and PCs (15)(16)(17). Furthermore, Mir-15a/16-1 null mice develop lymphoproliferative pathologies, although with low penetrance and indolent disease course.…”

Section: Introductionmentioning

confidence: 72%

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: Introductionmentioning

confidence: 72%

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 miR-146a sponge construct was designed based on the mature miR-146a sequence, with the addition of a central bulged mismatch. Partially overlapping forward and reverse primers were used as template for a concameric PCR as described 66 . The final PCR product was cloned downstream the mCherry reporter gene into a dual-reporter lentiviral vector.…”

Section: Methodsmentioning

confidence: 99%

A molecular network regulating the proinflammatory phenotype of human memory T lymphocytes

et al. 2020

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Understanding the mechanisms that modulate T helper lymphocyte functions is crucial to decipher normal and pathogenic immune responses in humans. To identify molecular determinants influencing the pathogenicity of T cells, we separated ex vivo -isolated primary human memory T lymphocytes based on their ability to produce high levels of inflammatory cytokines. We found that the inflammatory, cytokine-producing phenotype of memory T lymphocytes was defined by a specific core gene signature and was mechanistically regulated by the constitutive activation of the NF-κB pathway and by the expression of the transcriptional repressor BHLHE40. BHLHE40 attenuated the expression of anti-inflammatory factors, including miR-146a, a negative regulator of NF-κB activation, and ZC3H12D, an RNase of the Regnase-1 family able to degrade inflammatory transcripts. Our data reveal a molecular network regulating the pro-inflammatory phenotype of human memory T lymphocytes, with the potential to contribute to disease.

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“…Beyond CLL, a tumor-suppressive function of the miR-15 family has also been described for several other malignancies, which may be explained by its repressive effect on many proto-oncogenes such as Bcl2, Mcl1, c-Myb, and the cyclins D1, D3, and E3 [10][11][12]. The miR-15b/16-2 cluster, for example, has been described as a tumor suppressor in glioma and osteosarcoma, whereas the miR-497/195 cluster appears to suppress tumor development in hepatocellular carcinoma, colorectal cancer, breast cancer, melanoma, and many other tumor types [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…In addition to its role in cancer, recent data begin to unravel physiological functions of the miR-15 family, in particular miR-15a/16-1 and miR-15b/16-2. In early B-cell development, for example, a knockdown of the miR-15 family results in impaired differentiation and enhanced proliferation of pre-B cells [11], suggesting that miR-15 family members may preserve tissue homeostasis. Along the same line, the knockout of the miR-15a/16-1 cluster was reported to partially block natural killer (NK) cell maturation in the spleen [16].…”

Section: Introductionmentioning

confidence: 99%

Differential roles of miR‐15a/16‐1 and miR‐497/195 clusters in immune cell development and homeostasis

et al. 2020

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MicroRNAs (miRNAs) post-transcriptionally repress almost all genes in mammals and thereby form an additional layer of gene regulation. As such, miRNAs impact on nearly every physiological process and have also been associated with cancer. Prominent examples of such miRNAs can be found in the miR-15 family, composed of the bicistronic clusters miR-15a/ 16-1, miR-15b/16-2, and miR-497/195. In particular, the miR-15a/16-1 cluster is deleted in almost two thirds of all chronic B lymphocytic leukemia (CLL) cases, a phenotype that is also recapitulated by miR-15a/16-1deficient as well as miR-15b/16-2-deficient mice. Under physiological conditions, those two clusters have been implicated in T-cell function, and B-cell and natural killer (NK) cell development; however, it is unclear whether miR-497 and miR-195 confer similar roles in health and disease. Here, we have generated a conditional mouse model for tissue-specific deletion of miR-497 and miR-195. While mice lacking miR-15a/16-1 in the hematopoietic compartment developed clear signs of CLL over time, aging mice deficient for miR-497/195 did not show such a phenotype. Likewise, loss of miR-15a/16-1 impaired NK and early B-cell development, whereas miR-497/195 was dispensable for these processes. In fact, a detailed analysis of miR-497/195-deficient mice did not reveal any effect on steady-state hematopoiesis or immune cell function. Unexpectedly, even whole-body deletion of the cluster was well-tolerated and had no obvious impact on embryonic development or healthy life span. Therefore, we postulate that the miR-497/195 cluster is redundant to its paralog clusters or that its functional relevance is restricted to certain physiological and pathological conditions.

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The miR‐15 family reinforces the transition from proliferation to differentiation in pre‐B cells

Cited by 35 publications

References 69 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

A molecular network regulating the proinflammatory phenotype of human memory T lymphocytes

Differential roles of miR‐15a/16‐1 and miR‐497/195 clusters in immune cell development and homeostasis

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