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001-es BibID:	BIBFORM077169
035-os BibID:	(WoS)000460110400026 (Scopus)85063936796
Első szerző:	Jambrovics Károly (biológus, gyógyszer-biotechnológus)
Cím:	Transglutaminase 2 programs differentiating acute promyelocytic leukemia cells in all-trans retinoic acid treatment to inflammatory stage through NF-kB activation / Jambrovics Károly, Uray Iván P., Keresztessy Zsolt, Keillor Jeffrey W., Fésüs László, Balajthy Zoltán
Dátum:	2019
ISSN:	0390-6078
Megjegyzések:	Differentiation syndrome is a life-threatening complication arising during retinoid treatment of acute promyelocytic leukemia. Administration of all-trans retinoic acid leads to significant changes in gene expression, among the most induced of which is transglutaminase 2, which is not normally expressed in neutrophil granulocytes. To evaluate the pathophysiological function of transglutaminase 2 in the context of immunological function and disease outcomes, such as excessive superoxide anion, cytokine, and chemokine production in differentiated NB4 cells, we used an NB4 transglutaminase knock-out cell line and a transglutaminase inhibitor, NC9, which inhibits both transamidase- and guanosine triphosphate-binding activities, to clarify transglutaminase's contribution to the development of potentially lethal differentiation syndrome during all-trans retinoic acid treatment of acute promyelocytic leukemia. We found that such treatment not only enhanced cell-surface expression of CD11b and CD11c but also induced high-affinity states; atypical transglutaminase 2 expression in NB4 cells activated the nuclear factor kappa-light-chain-enhancer of activated B cells pathway, driving pathogenic processes with an inflammatory cascade through the expression of numerous cytokines, including Tumor necrosis factor alpha, Interleukin 1 beta, and Monocyte chemoattractant protein 1. NC9 decreased the amount of transglutaminase 2, p65/RelA, and p50 in differentiated NB4 cells and their nuclei, leading to attenuated inflammatory cytokine synthesis. NC9 significantly inhibits transglutaminase 2 nuclear translocation but accelerates its proteasomal breakdown. This study demonstrates that transglutaminase 2 expression induced by all-trans retinoic acid treatment reprograms inflammatory signaling networks governed by nuclear factor kappa-light-chain-enhancer of activated B cells activation, resulting in over-expression of tumor necrosis factor alpha and Interleukin 1 beta in differentiating acute promyelocytic leukemia cells, suggesting that atypically expressed transglutaminase 2 is a promising target for leukemia treatment.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk
Megjelenés:	Haematologica-The Hematology Journal. - 104 : 3 (2019), p. 505-515. -
További szerzők:	Uray Iván Péter (1970-) (kutatóorvos) Keresztessy Zsolt Keillor, Jeffrey W. Fésüs László (1947-) (orvos biokémikus) Balajthy Zoltán (1957-) (biokémikus, sejtbiológus)
Pályázati támogatás:	GINOP-2.3.2-15-2016-00020 GINOP TÁMOP-4.2.2.D-15/1/KONV-2015-0016 TÁMOP EFOP-3.6.1-16-2016-00022 EFOP GINOP-2.3.2-15-2016-00006 GINOP NK105046 OTKA
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