Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics

Robles, Eloy F.; Mena-Varas, Maria; Barrio, Laura; Merino-Cortes, Sara V.; Balogh, Péter; Du, Ming; Akasaka, Takashi; Parker, Antón; Roa, Sergio; Panizo, Carlos; Martín-Guerrero, Idoia; Siebert, Reiner; Segura, Víctor; Agirre, Xabier; Macri-Pellizeri, Laura; Aldaz, Beatriz; Vilas-Zornoza, Amaia; Zhang, Shaowei; Moody, Sarah; Calasanz, Marı́a José; Tousseyn, Thomas; Broccardo, Cyril; Brousset, Pierre; Campos-Sanchez, Elena; Cobaleda, César; Sánchez-Garcı́a, Isidro; Fernández-Luna, José L.; García‐Muñoz, Ricardo; Peña, Esther; Bellosillo, Beatríz; Salar, Antonio; Baptista, Maria João; Hernández-Rivas, Jesús María; González, Marcos; Terol, María José; Climent, Joan; Ferrández, Antonio; Sagaert, Xavier; Melnick, Ari; Prósper, Felipe; Oscier, David; Carrasco, Yolanda R.; Dyer, Martin J. S.; Martínez-Climent, José A.

doi:10.1038/ncomms11889

Cited by 43 publications

(41 citation statements)

References 52 publications

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“…These results are in line with previous work emphasizing the role of endothelial MAdCAM-1-a4b7 interactions in the transition of CPs to ILFs (5) and were comparable to the phenotype of MAdCAM-1-deficient mice. The lack of detectable Nkx2.3 in mature normal B cells also points to stromal factors responsible for impaired follicle maturation in these mutants (37).…”

Section: Discussionmentioning

confidence: 97%

IL-22–Independent Protection from Colitis in the Absence of Nkx2.3 Transcription Factor in Mice

Kellermayer

Vojkovics

Dakah

et al. 2019

The Journal of Immunology

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The transcription factor Nkx2.3 regulates the vascular specification of Peyer patches in mice through determining endothelial addressin preference and may function as a susceptibility factor in inflammatory bowel diseases in humans. We wished to analyze the role of Nkx2.3 in colonic solitary intestinal lymphoid tissue composition and in colitis pathogenesis. We studied the colonic solitary intestinal lymphoid tissue of Nkx2.3-deficient mice with immunofluorescence and flow cytometry. Colitis was induced in mice using 2.5% dextran sodium sulfate, and severity was assessed with histology, flow cytometry, and quantitative PCR. We found that the lack of Nkx2.3 impairs maturation of isolated lymphoid follicles and attenuates dextran sodium sulfate-induced colitis independent of endothelial absence of mucosal addressin cell-adhesion molecule-1 (MAdCAM-1), which was also coupled with enhanced colonic epithelial regeneration. Although we observed increased numbers of group 3 innate lymphoid cells and Th17 cells and enhanced transcription of IL-22, Ab-mediated neutralization of IL-22 did not abolish the protection from colitis in Nkx2.3-deficient mice. Nkx2.3 2/2 hematopoietic cells could not rescue wild-type mice from colitis. Using LacZ-Nkx2.3 reporter mice, we found that Nkx2.3 expression was restricted to VAP-1 + myofibroblast-like pericryptal cells. These results hint at a previously unknown stromal role of Nkx2.3 as driver of colitis and indicate that Nkx2.3 + stromal cells play a role in epithelial cell homeostasis.

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Section: Discussionmentioning

confidence: 97%

IL-22–Independent Protection from Colitis in the Absence of Nkx2.3 Transcription Factor in Mice

Kellermayer

Vojkovics

Dakah

et al. 2019

The Journal of Immunology

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“…It is likely that marginal zone-specific factors shape the phenotype of leukemic cells and facilitate their niche-specific retention. In this context, the homeobox protein NKX2-3, which acts as an oncogene, promotes marginal zone-lymphomagenesis by activating B-cell receptor signaling [29]. This, in turn, activates relevant adhesion molecules such as VLA-4 and CXCR4, in a Lyn/Syk-dependent way, eventually driving malignant transformation through triggering NF-κB and PI3K-AKT pathways.…”

Section: Marginal Zone B Cells and Other Mature B Cell Subsetsmentioning

confidence: 99%

VLA-4 Expression and Activation in B Cell Malignancies: Functional and Clinical Aspects

Härzschel

Zucchetto

Gattei

et al. 2020

IJMS

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Lineage commitment and differentiation of hematopoietic cells takes place in well-defined microenvironmental surroundings. Communication with other cell types is a vital prerequisite for the normal functions of the immune system, while disturbances in this communication support the development and progression of neoplastic disease. Integrins such as the integrin very late antigen-4 (VLA-4; CD49d/CD29) control the localization of healthy as well as malignant B cells within the tissue, and thus determine the patterns of organ infiltration. Malignant B cells retain some key characteristics of their normal counterparts, with B cell receptor (BCR) signaling and integrin-mediated adhesion being essential mediators of tumor cell homing, survival and proliferation. It is thus not surprising that targeting the BCR pathway using small molecule inhibitors has proved highly effective in the treatment of B cell malignancies. Attenuation of BCR-dependent lymphoma–microenvironment interactions was, in this regard, described as a main mechanism critically contributing to the efficacy of these agents. Here, we review the contribution of VLA-4 to normal B cell differentiation on the one hand, and to the pathophysiology of B cell malignancies on the other hand. We describe its impact as a prognostic marker, its interplay with BCR signaling and its predictive role for novel BCR-targeting therapies, in chronic lymphocytic leukemia and beyond.

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“…In SMZL, NKX2-3 is aberrantly activated by chromosomal translocation t(10;14)(q24;q32), juxtaposing the locus of this NKL homeobox gene to that of IGH [101]. Downstream analyses indicated aberrant activation of B-cell receptor signalling, enhanced expression of integrins, adhesion factor MADCAM1, and of chemokine receptor CXCR4 [101]. These features may underlie malignant transformation and homing of the tumor cells to the spleen and lymph nodes.…”

Section: Deregulated Nkl Homeobox Genes In B-cell Malignanciesmentioning

confidence: 99%

“…These features may underlie malignant transformation and homing of the tumor cells to the spleen and lymph nodes. In addition to SMZL, aberrant expression of NKX2-3 has been detected in DLBCL, FL, MCL, chronic lymphoid leukemia, and multiple myeloma (MM) [101]. Furthermore, deregulated expression of NKX2-3 has been associated with Crohn disease, ulcerative colitis and inflammatory bowel disease [102].…”

Section: Deregulated Nkl Homeobox Genes In B-cell Malignanciesmentioning

confidence: 99%

“…Aberrant activity of BARX2 has been found in HCL and MCL patients [39]. Furthermore, BARX2 and NKX2-3 were the only NKL homeobox genes aberrantly expressed in MM [101,108]. Interestingly, except for BARX2, MM and primary effusion lymphoma cell lines lacked activity of any NKL-code member, indicating aberrant downregulation of HHEX and NKX6-3.…”

Section: Deregulated Nkl Homeobox Genes In B-cell Malignanciesmentioning

confidence: 99%

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Deregulated NKL Homeobox Genes in B-Cell Lymphoma

Nagel

Drexler

2019

Cancers

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Recently, we have described physiological expression patterns of NKL homeobox genes in early hematopoiesis and in subsequent lymphopoiesis. We identified nine genes which constitute the so-called NKL-code. Aberrant overexpression of code-members or ectopically activated non-code NKL homeobox genes are described in T-cell leukemia and in T- and B-cell lymphoma, highlighting their oncogenic role in lymphoid malignancies. Here, we introduce the NKL-code in normal hematopoiesis and focus on deregulated NKL homeobox genes in B-cell lymphoma, including HLX, MSX1 and NKX2-2 in Hodgkin lymphoma; HLX, NKX2-1 and NKX6-3 in diffuse large B-cell lymphoma; and NKX2-3 in splenic marginal zone lymphoma. Thus, the roles of various members of the NKL homeobox gene subclass are considered in normal and pathological hematopoiesis in detail.

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Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics

Cited by 43 publications

References 52 publications

IL-22–Independent Protection from Colitis in the Absence of Nkx2.3 Transcription Factor in Mice

IL-22–Independent Protection from Colitis in the Absence of Nkx2.3 Transcription Factor in Mice

VLA-4 Expression and Activation in B Cell Malignancies: Functional and Clinical Aspects

Deregulated NKL Homeobox Genes in B-Cell Lymphoma

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