TY  - JOUR
A1  - Giampaolo, Sabrina
A1  - Wójcik, Gabriela
A1  - Klein-Hessling, Stefan
A1  - Serfling, Edgar
A1  - Patra, Amiya K.
T1  - B cell development is critically dependent on NFATc1 activity
JF  - Cellular & Molecular Immunology
N2  - B cell development in bone marrow is a precisely regulated complex process. Through successive stages of differentiation, which are regulated by a multitude of signaling pathways and an array of lineage-specific transcription factors, the common lymphoid progenitors ultimately give rise to mature B cells. Similar to early thymocyte development in the thymus, early B cell development in bone marrow is critically dependent on IL-7 signaling. During this IL-7-dependent stage of differentiation, several transcription factors, such as E2A, EBF1, and Pax5, among others, play indispensable roles in B lineage specification and maintenance. Although recent studies have implicated several other transcription factors in B cell development, the role of NFATc1 in early B cell developmental stages is not known. Here, using multiple gene-manipulated mouse models and applying various experimental methods, we show that NFATc1 activity is vital for early B cell differentiation. Lack of NFATc1 activity in pro-B cells suppresses EBF1 expression, impairs immunoglobulin gene rearrangement, and thereby preBCR formation, resulting in defective B cell development. Overall, deficiency in NFATc1 activity arrested the pro-B cell transition to the pre-B cell stage, leading to severe B cell lymphopenia. Our findings suggest that, along with other transcription factors, NFATc1 is a critical component of the signaling mechanism that facilitates early B cell differentiation.
KW  - differentiation
KW  - EBF1
KW  - NFATc1
KW  - pro-B
KW  - pre-B
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233006
VL  - 16
ER  - 
TY  - JOUR
A1  - Barahona de Brito, Carlotta
A1  - Klein-Hessling, Stefan
A1  - Serfling, Edgar
A1  - Patra, Amiya Kumar
T1  - Hematopoietic stem and progenitor cell maintenance and multiple lineage differentiation is an integral function of NFATc1
JF  - Cells
N2  - Hematopoietic stem and progenitor cell (HSPC) maintenance and the differentiation of various lineages is a highly complex but precisely regulated process. Multiple signaling pathways and an array of transcription factors influence HSPC maintenance and the differentiation of individual lineages to constitute a functional hematopoietic system. Nuclear factor of activated T cell (NFAT) family transcription factors have been studied in the context of development and function of multiple mature hematopoietic lineage cells. However, until now their contribution in HSPC physiology and HSPC differentiation to multiple hematopoietic lineages has remained poorly understood. Here, we show that NFAT proteins, specifically NFATc1, play an indispensable role in the maintenance of HSPCs. In the absence of NFATc1, very few HSPCs develop in the bone marrow, which are functionally defective. In addition to HSPC maintenance, NFATc1 also critically regulates differentiation of lymphoid, myeloid, and erythroid lineage cells from HSPCs. Deficiency of NFATc1 strongly impaired, while enhanced NFATc1 activity augmented, the differentiation of these lineages, which further attested to the vital involvement of NFATc1 in regulating hematopoiesis. Hematopoietic defects due to lack of NFATc1 activity can lead to severe pathologies such as lymphopenia, myelopenia, and a drastically reduced lifespan underlining the critical role NFATc1 plays in HSPC maintenance and in the differentaion of various lineages. Our findings suggest that NFATc1 is a critical component of the myriad signaling and transcriptional regulators that are essential to maintain normal hematopoiesis.
KW  - hematopoiesis
KW  - HSC
KW  - lineage differentiation
KW  - NFATc1
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-278809
SN  - 2073-4409
VL  - 11
IS  - 13
ER  - 
TY  - JOUR
A1  - Murti, Krisna
A1  - Fender, Hendrik
A1  - Glatzle, Carolin
A1  - Wismer, Rhoda
A1  - Sampere-Birlanga, Salvador
A1  - Wild, Vanessa
A1  - Muhammad, Khalid
A1  - Rosenwald, Andreas
A1  - Serfling, Edgar
A1  - Avots, Andris
T1  - Calcineurin-independent NFATc1 signaling is essential for survival of Burkitt lymphoma cells
JF  - Frontiers in Oncology
N2  - In Burkitt lymphoma (BL), a tumor of germinal center B cells, the pro-apoptotic properties of MYC are controlled by tonic B cell receptor (BCR) signals. Since BL cells do not exhibit constitutive NF-κB activity, we hypothesized that anti-apoptotic NFATc1 proteins provide a major transcriptional survival signal in BL. Here we show that post-transcriptional mechanisms are responsible for the calcineurin (CN) independent constitutive nuclear over-expression of NFATc1 in BL and Eµ-MYC – induced B cell lymphomas (BCL). Conditional inactivation of the Nfatc1 gene in B cells of Eµ-MYC mice leads to apoptosis of BCL cells in vivo and ex vivo. Inhibition of BCR/SYK/BTK/PI3K signals in BL cells results in cytosolic re-location of NFATc1 and apoptosis. Therefore, NFATc1 activity is an integrated part of tonic BCR signaling and an alternative target for therapeutic intervention in BL.
KW  - apoptosis
KW  - Burkitt lymphoma
KW  - cyclosporin A
KW  - nuclear localization
KW  - NFATc1
KW  - activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL)
KW  - B cell receptor (BCR)
KW  - Burkitt lymphoma (BL)
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323103
VL  - 13
ER  -