TY  - JOUR
AB  - The development and regulation of malignant self-renewal remains an unresolved issue. Here, we provide biochemical, genetic, and functional evidence that dynamics in ribosomal RNA (rRNA) 2'-O-methylation regulate leukemia stem cell (LSC) activity in vivo. A comprehensive analysis of the rRNA 2'-O-methylation landscape of 94 acute myeloid leukemia (AML) patients revealed dynamic 2'-O-methylation specifically at exterior sites of ribosomes. rRNA 2'-O-methylation pattern is closely associated with AML development stage and LSC gene expression signature. Forced expression of 2'-O-methyltransferase FBL induced an AML stem cell phenotype and enabled engraftment of non-LSC leukemia cells in NSG mice. Enhanced 2'-O-methylation redirected the ribosome translation program towards amino acid transporter mRNAs enriched in optimal codons and subsequently increased intracellular amino acid levels. Methylation at the single site 18S-guanosine 1447 was instrumental for LSC activity. Collectively, our work demonstrates that dynamic 2'-O-Me at specific sites on ribosomal RNAs shifts translational preferences and controls AML-LSC self-renewal.
AU  - Zhou, F.*
AU  - Aroua, N.*
AU  - Liu, Y.*
AU  - Rohde, C.*
AU  - Cheng, J.*
AU  - Wirth, A.-K.
AU  - Fijalkowska, D.*
AU  - Göllner, S.*
AU  - Lotze, M.T.*
AU  - Yun, H.*
AU  - Yu, X.*
AU  - Pabst, C.*
AU  - Sauer, T.*
AU  - Oellerich, T.*
AU  - Serve, H.*
AU  - Röllig, C.*
AU  - Bornhäuser, M.*
AU  - Thiede, C.*
AU  - Baldus, C.*
AU  - Frye, M.*
AU  - Raffel, S.*
AU  - Krijgsveld, J.*
AU  - Jeremias, I.
AU  - Beckmann, R.*
AU  - Trumpp, A.*
AU  - Müller-Tidow, C.*
C1  - 66477
C2  - 52829
CY  - 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
SP  - 1–17
TI  - A dynamic rRNA ribomethylome drives stemness in acute myeloid leukemia.
JO  - Cancer Discov.
VL  - 13
IS  - 2
PB  - Amer Assoc Cancer Research
PY  - 2023
SN  - 2159-8274
ER  - 

TY  - JOUR
AB  - Cancer-associated inflammation is a molecular key feature in pancreatic ductal adenocarcinoma. Oncogenic KRAS in conjunction with persistent inflammation is known to accelerate carcinogenesis, although the underlying mechanisms remain poorly understood. Here, we outline a novel pathway whereby the transcription factors NFATc1 and STAT3 cooperate in pancreatic epithelial cells to promote Kras G12D - driven carcinogenesis. NFATc1 activation is induced by inflammation and itself accelerates inflammation-induced carcinogenesis in KrasG12D mice, whereas genetic or pharmacologic ablation of NFATc1 attenuates this effect. Mechanistically, NFATc1 complexes with STAT3 for enhancer-promoter communications at jointly regulated genes involved in oncogenesis, for example, Cyclin, EGFR and WNT family members. The NFATc1-STAT3 cooperativity is operative in pancreatitis-mediated carcinogenesis as well as in established human pancreatic cancer. Together, these studies unravel new mechanisms of inflammatory-driven pancreatic carcinogenesis and suggest beneficial effects of chemopreventive strategies using drugs that are currently available for targeting these factors in clinical trials. SIGNIFICANCE: Our study points to the existence of an oncogenic NFATc1-STAT3 cooperativity that mechanistically links inflammation with pancreatic cancer initiation and progression. Because NFATc1-STAT3 nucleoprotein complexes control the expression of gene networks at the intersection of inflammation and cancer, our study has signifi cant relevance for potentially managing pancreatic cancer and other inflammatory-driven malignancies.
AU  - Baumgart, S.*
AU  - Chen, N.*
AU  - Siveke, J.T.*
AU  - König, A.O.*
AU  - Zhang, J.*
AU  - Singh, S.K.*
AU  - Wolf, E.*
AU  - Bartkuhn, M.*
AU  - Esposito, I.
AU  - Heßmann, E.*
AU  - Reinecke, J.*
AU  - Nikorowitsch, J.*
AU  - Brunner, M.*
AU  - Singh, G.P.*
AU  - Fernández-Zapico, M.E.*
AU  - Smyrk, T.C.*
AU  - Bamlet, W.R.*
AU  - Eilers, M.*
AU  - Neeße, A.*
AU  - Gress, T.M.*
AU  - Billadeau, D.D.*
AU  - Tuveson, D.A.*
AU  - Urrutia, R.A.*
AU  - Ellenrieder, V.*
C1  - 32704
C2  - 35583
SP  - 688-701
TI  - Inflammation-induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D.
JO  - Cancer Discov.
VL  - 4
IS  - 6
PY  - 2014
SN  - 2159-8274
ER  -