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Genetic and Epigenetic Characterization of a Discordant KMT2A/AFF1-Rearranged Infant Monozygotic Twin Pair.

ABSTRACT: The KMT2A/AFF1 rearrangement is associated with an unfavorable prognosis in infant acute lymphocytic leukemia (ALL). Discordant ALL in monozygotic twins is uncommon and represents an attractive resource to evaluate intrauterine environment-genetic interplay in ALL. Mutational and epigenetic profiles were characterized for a discordant KMT2A/AFF1-rearranged infant monozygotic twin pair and their parents, and they were compared to three independent KMT2A/AFF1-positive ALL infants, in which the DNA methylation and gene expression profiles were investigated. A de novo Q61H NRAS mutation was detected in the affected twin at diagnosis and backtracked in both twins at birth. The KMT2A/AFF1 rearrangement was absent at birth in both twins. Genetic analyses conducted at birth gave more insights into the timing of the mutation hit. We identified correlations between DNA methylation and gene expression changes for 32 genes in the three independent affected versus remitted patients. The strongest correlations were observed for the RAB32, PDK4, CXCL3, RANBP17, and MACROD2 genes. This epigenetic signature could be a putative target for the development of novel epigenetic-based therapies and could help in explaining the molecular mechanisms characterizing ALL infants with KMT2A/AFF1 fusions.

SUBMITTER: Russo A

PROVIDER: S-EPMC8466096 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Inhibition of the H3K79 histone methyltransferase DOT1L has exhibited encouraging preclinical and early clinical activity in KMT2A (MLL)-rearranged leukemia, supporting the development of combinatorial therapies. Here, we investigated two novel combinations: dual inhibition of the histone methyltransferases DOT1L and EZH2, and the combination with a protein synthesis inhibitor. EZH2 is the catalytic subunit in the polycomb repressive complex 2 (PRC2), and inhibition of EZH2 has been reported to have preclinical activity in KMT2A-r leukemia. When combined with DOT1L inhibition, however, we observed both synergistic and antagonistic effects. Interestingly, antagonistic effects were not due to PRC2-mediated de-repression of HOXA9. HOXA cluster genes are key canonical targets of both KMT2A and the PRC2 complex. The independence of the HOXA cluster from PRC2 repression in KMT2A-r leukemia thus affords important insights into leukemia biology. Further studies revealed that EZH2 inhibition counteracted the effect of DOT1L inhibition on ribosomal gene expression. We thus identified a previously unrecognized role of DOT1L in regulating protein production. Decreased translation was one of the earliest effects measurable after DOT1L inhibition and specific to KMT2A-rearranged cell lines. H3K79me2 chromatin immunoprecipitation sequencing patterns over ribosomal genes were similar to those of the canonical KMT2A-fusion target genes in primary AML patient samples. The effects of DOT1L inhibition on ribosomal gene expression prompted us to evaluate the combination of EPZ5676 with a protein translation inhibitor. EPZ5676 was synergistic with the protein translation inhibitor homoharringtonine (omacetaxine), supporting further preclinical/clinical development of this combination. In summary, we discovered a novel epigenetic regulation of a metabolic process-protein synthesis-that plays a role in leukemogenesis and affords a combinatorial therapeutic opportunity.

Project description:PurposeMonozygotic (MZ) twin pairs discordant for disease allow careful examination of environmental factors whilst controlling for genetic variation. The purpose of this study was to examine differences in environmental risk factors in MZ twins discordant for myopia.MethodsSixty four MZ twin pairs discordant for refractive error were interviewed. Discordant twins were selected from 1326 MZ twin pairs from the TwinsUK adult twin registry with non-cycloplegic autorefraction. Discordancy was defined as ? 2 Dioptres (D) difference in spherical equivalent (SphE) and discordant for class of refractive error. In a 35-item telephone questionnaire twins were separately asked (and scored) about the risk factors urban/rural residence, occupational status and highest educational level. They responded with more (1), less (-1) or the same (0) as their twin on time spent outside, playing outdoor sport, and on close work aged <16 and 16-25 years. The lower SphE twin's score was subtracted from the higher SphE twin's score, and mean values of the difference calculated for each variable.ResultsSixty four twin pairs were included (mean age 56, range 30-79 years; mean difference in refraction 3.35 D, S.D. 1.55 D, median difference 2.78 D). Within discordant MZ twin pairs, the more myopic twin was associated with having a higher occupational status (mean score between 16 and 25 years -0.11; 95% CI -0.19 to -0.04; mean score aged >25 years -0.23, 95% CI -0.28 to -0.17), being resident in urban area (mean score -0.26; 95% CI -0.33 to -0.18) and performing more close work (mean score <16 years -0.11; 95% CI -0.18 to -0.05; mean score aged 16-25 years -0.17, 95% CI -0.24 to -0.10) than their twin. The twins who spent more time outdoors (mean score <16 years 0.09; 95% CI 0.03-0.15; mean score aged 16-25 years 0.28, 95% CI 0.15-0.41) or performed more outdoors sports (mean score <16 years 0.13; 95% CI 0.04-0.21; mean score aged 16-25 years 0.23, 95% CI 0.10-0.36) were less likely to be myopic than their twin.ConclusionsThis study has confirmed known environmental risk factors for myopia. These data will allow selection of discordant twins for epigenetic analysis to advance knowledge of mechanisms of refractive error development.

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Genetic and Epigenetic Characterization of a Discordant KMT2A/AFF1-Rearranged Infant Monozygotic Twin Pair.

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