NOP2/Sun RNA methyltransferase family member 2 (NSUN2) catalyzes 5-methylcytosine (m5C) modifications on RNA to regulate mRNA stability. However, its roles in normal hematopoiesis and leukemogenesis remain poorly understood. Here, we show that NSUN2 is markedly upregulated in primary AML patient samples compared with normal hematopoietic cells. NSUN2 knockdown (KD) impaired AML cell proliferation, induced apoptosis, and reduced colony formation. Genetic ablation of Nsun2 in an MLL-AF9 (MA9)-transformed murine AML model substantially impaired leukemia stem cell (LSC) self-renewal and prolonged overall survival (OS), while sparing normal hematopoiesis, highlighting NSUN2 as a potential therapeutic target. Notably, wild-type NSUN2, but not catalytically inactive mutants, restored LSC function and leukemogenesis in NSUN2-deficient AML cells, indicating that these effects are m􀀀C-dependent. Mechanistically, NSUN2 stabilized FosB proto-oncogene (FOSB) mRNA via m􀀀C modification at nucleotide 3656 in the 3′-UTR, thereby upregulating FOSB expression. In turn, FOSB transcriptionally activated NSUN2, forming a feedforward regulatory loop. Furthermore, FOSB promoted expression of the anti-apoptotic regulator B-cell lymphoma-2-like protein 1 (BCL2L1) by directly binding to its promoter. In conclusion, these findings uncover a novel NSUN2-FOSB-BCL2L1 axis that drives AML leukemogenesis in an m5C-dependent manner, suggesting the therapeutic potential for targeting this pathway.
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Understanding how mature megakaryocytes (MKs) release their platelets, and crucially, what are the triggers that facilitate this process is of huge impact on human medicine. Controlling this biological process, as well as being able to utilise in vitro produced platelets will be a major therapeutic advancement. Unfortunately, the exact mechanism and mediators that drive thrombopoiesis remain elusive. Here, we seek to identify such mediators through studying the dynamics of platelet production after an acute loss of platelets. Analysis of plasma taken from 19 plateletpheresis donors at various timepoints pre and post donation, identified peak platelet production timepoints (4-8 hours). Analysis of these timepoints by proteomic and metabolomic techniques allowed for the identification of Triiodothyronine (T3), as well as its analogues, GC-1 (Sobetirome), MGL-3196 (Resmetirom) and KB2115 (Eprotirome), as having a direct effect on in vitro platelet production in human cord blood (T3 3 hours 100nM 1.26±0.24 and GC-1 100μM 5.54±1.58, MGL-3196 300μM 6.92±1.38, KB2115 75μM 17.90±5.25 fold change at 12 hours, mean±SD) and iPSC-derived MKs (viral A1ATD1 KB2115 36.1uM 3.36±0.38, inducible QOLG1.1H KB2115 75uM 1.85±0.46 fold change, mean±SD). Receptor specific antagonists revealed that thyroid hormone induced platelet production primarily signals via the non-genomic signalling pathway, integrin αVβ3 (CD51/61, vitronectin receptor), of which MKs highly express. When combined with silk-based-3-dimensional scaffold bioreactor technology, we observe a significant upscaling of platelets (KB2115 2.8±0.79 fold change±SD) that respond positively to agonist stimulation (P-selectin exposure). This shows the direct impact of thyroid on platelet production through integrin αVβ3, which offers interesting therapeutic potential in the field of transfusion medicine.
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