RNA methylation in lymphoid malignancies

Abstract

Further, an mRNA demethylase, Fat mass and obesity associated enzyme (FTO) mRNA expression was found to be high in lymphoma cells compared to normal B cells. A similar trend was also observed between normal and ALL patients at diagnosis. Overall, our studies suggest that altered RNA methylation and enzymes controlling this process may be of significance in the pathology of lymphoid malignancies.

1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors

“…The crude residue was purified by flash column chromatography (DCM/MeOH = 100:5 to 100:8 to 100:10 to 100:15) to afford the desired product as a white solid (4.14 g, 55% yield over two steps). 1 H NMR (400 MHz, CDCl 3 ): δ 6.00 (br s, 1H), 3.51 (s, 2H), 3.49−3.43 (m, 4H), 2.91 (s, 2H), 1.74−1.63 (m, 4H), 1.47 (s, 9H); 13 N-Benzyl-6-(4-(6-((4,4-dimethylpiperidin-1-yl)methyl)pyridin-3-yl)-1-oxa-4,9-diazaspiro [5.5]undecan-9-yl)pyrimidin-4-amine (7). The corresponding Boc protected amine was obtained following the general procedure for Buchwald−Hartwig coupling (chromatography: EtOAc/heptane = 7:3 to 9:1 to EtOAc/ MeOH = 100:0 to 100:1 to 100:5).…”

“…6 Therefore, it is not surprising that abnormal levels of m 6 A have been correlated with certain cancers, such as acute myeloid leukemia (AML) and lymphomas, among others. 5,7 Furthermore, other biological mechanisms may be influenced by m 6 A dysfunctional levels like the circadian clock, 8 stem cell differentiation, or even viral gene expression. 9 The dynamic and reversible nature of m 6 A is regulated by three types of proteins called ″writers″, ″readers″, and ″erasers″.…”

“…m 6 A has been found in all kinds of cellular RNA, including mRNA, tRNA, and rRNA, and its roles in gene expression regulation are various, ranging from splicing to translation, stability, and degradation . Therefore, it is not surprising that abnormal levels of m 6 A have been correlated with certain cancers, such as acute myeloid leukemia (AML) and lymphomas, among others. , Furthermore, other biological mechanisms may be influenced by m 6 A dysfunctional levels like the circadian clock, stem cell differentiation, or even viral gene expression …”

METTL3 inhibitors for epitranscriptomic modulation of cellular processes

“…2,3 It is also found in other RNA species including lncRNAs, 5 rRNAs, 6 and snRNAs. 7 Dysregulated m 6 A deposition is directly involved in the development of acute myeloid leukemia (AML) and lymphomas, difficult-to-treat blood cancers, 1, [8][9][10][11][12] as well being associated with other types of cancer (e.g., bladder, lung, ovarian, colorectal, bone, liver, gastric). [13][14][15][16][17][18][19][20][21] Figure 1.…”

“…[24][25][26] METTL3/14 plays a critical role in disorders associated with abnormal self-renewal, aberrant proliferation, and blocking differentiation of hematopoietic cells. 1, [8][9][10][11][12] AML and B-cell lymphoma are among the cancers with the highest expression of METTL3 based on The Cancer Genome Atlas database. 9 Both METTL3 and METTL14 were found to be upregulated in all subtypes of AML compared to normal hematopoietic cells, despite the heterogeneity of this blood cell cancer in terms of chromosomal rearrangement and gene mutations.…”