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. 2025 Jul 11;2(3):100136.
doi: 10.1016/j.bneo.2025.100136. eCollection 2025 Aug.

Elevated B12 serum levels are associated with the presence of clonal hematopoiesis

Varun Gupta  1 , Peter D Lyon  2   3 , Aristeidis G Telonis  3   4 , Marina Konopleva  1 , Luisa Cimmino  3   4
Affiliations

Elevated B12 serum levels are associated with the presence of clonal hematopoiesis

Varun Gupta et al. Blood Neoplasia. .
No abstract available

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Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
Examination of the AoU database reveals an association between elevated serum B12 levels and the prevalence of CH. In the AoU genomic database, 1256 individuals were positive for CH and had serum B12 information available. They were compared to 18 174 individuals without CH for whom B12 serum concentrations were also available. B12 levels were categorized into the following bins (pg/mL): 0 to 200, 201 to 400, 401 to 600. 601-800, 801-1000, and >1000 and used to determine CH prevalence (A) and OR (B), calculated by Fisher exact test, with significant adjusted P value obtained by pairwise Fisher exact test for comparisons made between normal B12 levels (200-800 pg/mL) vs above the normal levels (>1000 pg/mL), including 201 to 400 vs >1000 (OR, 1.37; P = .00525), 401 to 600 vs >1000 (OR, 1.45; P = .000545), and 601 to 800 vs >1000 (OR, 1.37; P = .009150) pg/mL (shown in red). (C) Median serum B12 concentrations in individuals with CH, MDS, and AML compared to nonmutant individuals (no mutation; median with upper and lower quartiles are shown, significance calculated by Wilcoxon test). (D) Frequency and mutational spectrum of CH individuals in the AoU database. (E-F) Stratification by median serum B12 concentration (pg/ml) per CH mutation (E) and comparison to other CH mutant or nonmutant individuals (median with upper and lower quartiles are shown, significance calculated by Wilcoxon test) (F). (G) Fold change in CH mutation frequency above vs below the median serum B12 concentration of individuals with CH (P < .05 [by 2 proportional test]). AML, acute myeloid leukemia; MDS, myelodysplastic syndrome.
Figure 2.
Figure 2.
Higher B12 serum levels increase clonal fitness in a CH mutant murine model. (A) B12 acts as a cofactor for 2 mammalian enzymes, MS and MCM. MS is the central regulator of one-carbon metabolism that coordinates folate with Met recycling after its processive conversion to SAM and Hcy. Met, upon its breakdown to PP-CoA and, subsequently, MM-CoA, is then converted to Succ-CoA by MCM for entry into the TCA cycle. (B) BM reconstitution assays were performed using CD45.2+Sf3b1+/+ or Sf3b1+/K700E donor cells mixed 1:5 with congenic WT CD45.1+ support BM (equivalent to 10% variant allele frequency). Upon confirmation of engraftment (4 weeks after transplant), altered B12 and Met dietary supplementation was initiated compared to a normal diet until 8 months after transplant (7 months of dietary intervention). (C) Serum B12 (pg/ml) measured by enzyme-linked immunosorbent assay in WT mice after 4 months of supplementation with high B12 and/or Met diets compared to normal chow. (D-F) Frequency of CD45.2+Sf3b1+/+ or Sf3b1+/K700E cells from mice fed high B12 and Met compared to a normal diet measured by flow cytometry in total cells (D) and CD11b+ cells (E) of peripheral blood, spleen, and BM at month 2 or month 8 after transplant; frequency of CD45.2+Sf3b1+/+ or Sf3b1+/K700E cells in BM Lin–, LK, LSK, hematopoietic stem cells (CD150+CD48–), and myeloid-primed multipotent progenitor cells (CD150–CD48+) at month 8 after transplant (F). (G-H) Fold change in competitiveness of CD45.2+Sf3b1+/+ or Sf3b1+/K700E cells at month 8 after transplant in CD11b+ cells (G) and BM hematopoietic stem and progenitor cells (H). Data shown are the mean and range of cell frequencies and fold changes. Student t test; ∗P < .05; ∗∗P < .01. BM, bone marrow; Hcy, homocysteine; Lin–, lineage negative; LK, ckit+Sca1–; LSK, Lin–cKit+Sca1+; Met, methionine; MM-CoA, methylmalonyl coenzyme A; MS, methionine synthase; PP-CoA, propionyl coenzyme A; SAM, s-adenosylmethionine; Succ-CoA, succinyl coenzyme A; TCA, Tricarboxylic acid cycle; WT, wild-type.
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