Enforced expression of Lin28b leads to impaired T-cell development, release of inflammatory cytokines, and peripheral T-cell lymphoma

Beachy, Sarah H.; Onozawa, Masahiro; Chung, Yun Kyung; Slape, Christopher; Bilke, Sven; Francis, Princy; Pineda, Marbin; Walker, Robert L.; Meltzer, Paul S.; Aplan, Peter D.

doi:10.1182/blood-2012-01-401760

Cited by 67 publications

(65 citation statements)

References 48 publications

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“…Previous studies have reported differences in the ability of ectopic Lin28 to induce hematologic malignancy(43,44,46). In our system, we did not observe malignancy in transplant recipients of mouse iLIN28B bone marrow, even after months ofLIN28B induction.…”

Section: Discussionmentioning

confidence: 95%

“…Some reports suggest that LIN28B overexpression can result in lymphoid malignancy (44,45), whereas other studies have not supported a role for Lin28 in hematologic malignancy (43,46). We show here that expression of LIN28B in adult mice drives accumulation of immature MCs, resulting in an overabundance of immature MCs that are hypofunctional upon antigen challenge in vivo .…”

Section: Introductionmentioning

confidence: 99%

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The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy

et al. 2015

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Mast cells are critical components of the innate immune system and important for host defense, allergy, autoimmunity, tissue regeneration, and tumor progression. Dysregulated mast cell development leads to systemic mastocytosis, a clinically variable but often devastating family of hematologic disorders. Here we report that induced expression of Lin28, a heterochronic gene and pluripotency factor implicated in driving a fetal hematopoietic program, caused mast cell accumulation in adult mice in target organs such as the skin and peritoneal cavity. In vitro assays revealed a skewing of myeloid commitment in LIN28B-expressing hematopoietic progenitors, with increased levels of LIN28B in common myeloid and basophil-mast cell progenitors altering gene expression patterns to favor cell fate choices that enhanced mast cell specification. In addition, LIN28B-induced mast cells appeared phenotypically and functionally immature, and in vitro assays suggested a slowing of mast cell terminal differentiation in the context of LIN28B upregulation. Finally, interrogation of human mast cell leukemia samples revealed upregulation of LIN28B in abnormal mast cells from patients with systemic mastocytosis (SM). This work identifies Lin28 as a novel regulator of innate immune function and a new protein of interest in mast cell disease.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy

et al. 2015

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“…Tg mice expressing Lin28b in the hematopoietic tissue by Vav-regulatory elements develop tumors of CD3 + CD4 + CD8 − follicular helper T-cells (T FH ) resembling human PTCL-NOS (or a specific subset) clinically and morphologically [16]. Lin28b is known to block production of the let-7 family of tumor suppressor micro-RNAs.…”

Section: Genetically Engineered Mouse Models For Mtclmentioning

confidence: 99%

Models for mature T-cell lymphomas—A critical appraisal of experimental systems and their contribution to current T-cell tumorigenic concepts

Warner¹,

Crispatzu²,

Al-Ghaili³

et al. 2013

Critical Reviews in Oncology/Hematology

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“…Given such heterogeneity, it is unclear whether the two paralogs play redundant or independent roles in the tumor development process. Transgenic overexpression of mouse or human forms of LIN28B have produced murine models of T-cell acute lymphoid leukemia (Beachy et al 2012), neuroblastoma (Molenaar et al 2012), Wilms tumor (Urbach et al 2014), hepatocellular carcinoma (Nguyen et al 2014), and intestinal tumors, but the earlier demonstration of intestinal tumorigenesis did not assess the role of LIN28A and concluded that LIN28B could act as an oncogene in the absence of other canonical genetic alterations (Madison et al 2013). Typically, cancers require perturbations in more than one oncogenic pathway, and, to date, the interaction between LIN28 and other oncogenic pathways during tumor development has not been rigorously defined.…”

mentioning

confidence: 99%

LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans

Schwitalla

Qian

et al. 2015

Genes Dev.

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Colorectal cancer (CRC) remains a major contributor to cancer-related mortality. LIN28A and LIN28B are highly related RNA-binding protein paralogs that regulate biogenesis of let-7 microRNAs and influence development, metabolism, tissue regeneration, and oncogenesis. Here we demonstrate that overexpression of either LIN28 paralog cooperates with the Wnt pathway to promote invasive intestinal adenocarcinoma in murine models. When LIN28 alone is induced genetically, half of the resulting tumors harbor Ctnnb1 (β-catenin) mutation. When overexpressed in Apc Min/+ mice, LIN28 accelerates tumor formation and enhances proliferation and invasiveness. In conditional genetic models, enforced expression of a LIN28-resistant form of the let-7 microRNA reduces LIN28-induced tumor burden, while silencing of LIN28 expression reduces tumor volume and increases tumor differentiation, indicating that LIN28 contributes to tumor maintenance. We detected aberrant expression of LIN28A and/or LIN28B in 38% of a large series of human CRC samples (n = 595), where LIN28 expression levels were associated with invasive tumor growth. Our late-stage CRC murine models and analysis of primary human tumors demonstrate prominent roles for both LIN28 paralogs in promoting CRC growth and progression and implicate the LIN28/let-7 pathway as a therapeutic target.

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Enforced expression of Lin28b leads to impaired T-cell development, release of inflammatory cytokines, and peripheral T-cell lymphoma

Cited by 67 publications

References 48 publications

The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy

The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy

Models for mature T-cell lymphomas—A critical appraisal of experimental systems and their contribution to current T-cell tumorigenic concepts

LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans

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