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Birçok kanser türünde deşifre edilen önemli mutasyon. TET2 geninin RNA paketlemesini etkilediğini ve mutasyonları kanser riskiyle ilişkilendirdiğini gösterdiler. news.uchicago.edu/story/uchica...

UChicago scientists decode key mutation in many cancers
UChicago scientists decode key mutation in many cancers

Finding points to expanded role of RNA in human gene expression

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DDmsmacrophage.bsky.social

Cool finding- People with newly diagnosed #rheumatoidarthritis have lots of TNF and had low level of Tet2 and other CHIP mutants that went down as they started anti-TNF or anti-inflammatory therapy! Proof this happens in humans too (8/n)

Figure 4. CH clones, including mutant TET2, become undetectable in the peripheral blood of older adults administered the TNF blocker, HUMIRA (adalimumab). Mutant-TET2, ASXL1, TP53, CBL, PPM1D, PHF6, and STAG2 clones identified in the peripheral whole blood of patients with RA before any immunomodulatory treatment (baseline) and at 3 and 6 months after treatment with the adalimumab (V1 and V2, respectively), show a significant reduction in CH clones after treatment. (A-B) Mean ± standard error of the mean (A) and detected mutant clones (B) shown. nd, none detected; V1, visit 1; V2, visit 2.
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DDmsmacrophage.bsky.social

Stem cells with Tet2 mutations could outcompete normal cells in old mice that had lots of TNF but not in TNF knockout mice. The aging inflammatory microenvironment contributes to CHIP! (7/n)

Figure 2. Tet2 mutations increase circulating myeloid cells of old WT but not TNF–/– recipient mice. Circulating myeloid immune populations were compared in young WT, old WT, and old TNF–/– recipient mice. (A-C) Total counts of circulating monocytes (A), Ly6Chigh monocytes (B), and neutrophils (C). (D-F) Total circulating monocytes, neutrophils, and Ly6Chigh monocytes as a proportion of total leukocytes (CD45+ ) cells, respectively. (G) Surface expression of F4/80 on Ly6Chigh monocyte. (H) Intracellular expression of TNF in monocytes after stimulation with lipopolysaccharides. Data are shown as a stacked bar plot, in which orange represents gated CD45.2 Tet2–/– cells and blue represents CD45.1 WT cells. Statistical significance determined by 2-way ANOVA with Tukey multiple comparisons test. Letters in the orange and blue columns denote significant differences (P ≤ .05) in the group means of CD45.2 or CD45.1 alleles, respectively. For all variables with the same letter, the difference b
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DDmsmacrophage.bsky.social

We investigated whether Tet2 mutant stem cells could outcompete others in the presence of the inflammatory cytokine TNF, which increases with age. We put a mix of normal and Tet2-/- stem cells into old mice that had lots of TNF and those with none (TNF KO). 6/n

gure 1. Age-associated TNF inflammation increases myeloid progenitor differentiation in female mice 8 weeks after BMT with WT and Tet2–/– HSPCs. (A) Experimental design and representative flow cytometric data showing CD45+ T-cell–depleted (TCD) BM donor cells transplanted in mice conditioned with busulfan. Young (6 months) and old (18-22 months) C57Bl/6-J WT and old TNF–/– animals received 80 mg/kg busulfan and received transplantation with 2 × 106 TCD-BM cells from young CD45.1+ WT and CD45.2+ Tet2–/– mice. (B) Histogram showing percentage of CD45.1+ WT and CD45.2 Tet2–/– donor cells transplanted into recipient mice. (C) Ratio of CD45.2+ Tet2–/– to CD45.1+ WT leukocytes in the BM of recipient mice 8 weeks after BMT. (D-I) Flow cytometric analyses showing absolute counts of HSPC (D), common myeloid progenitor (CMP) cells (E), monocyte-dendritic progenitor (MDP) cells (F), granulocyte-monocyte progenitor (GMP) cells (G), common monocyte progenitor (cMoP) cells (H), and mature monocytes
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DDmsmacrophage.bsky.social

With age the proportion of Tet2 mutant cells increases possibly bc the increased #inflammation that occurs with age contributes. Darwinian evolution happens in the bone marrow and stem cells with Tet2 mutations can outcompete ( replicate more, make more white blood cells) than those without (5/n)

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DDmsmacrophage.bsky.social

Hematopoetic #stemcells#monocytes#Bcells) and can outcompete stem cells that don't have Tet2 mutations.(3/n)

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DDmsmacrophage.bsky.social

Over time the progenitor cells (#stemcells) in our bone marrow acquire random mutations, with some genes being more likely to acquire these mutations than other. The Tet2 gene is one that acquires mutations. This is a problem because it regulates other genes through methylation (2/n)

Visual Abstract from Blood Advances Journal Article showing experimental outline studies in this manuscript.
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