Role of DOT1L in epigenetic regulation of the HOXA9 gene expression in mixed lineage leukemia
Bibliographic record
Abstract
Mixed lineage leukemia (MLL) is often characterized by chromosomal translocations involving the lysine methyltransferase 2A (KMT2A) gene with various partner genes, creating fusion proteins that can mistarget DOT1L to the homeobox A9 (HOXA9) gene, leading to HOXA9 expression. Among the possible translocations with KMT2A, the fusion of KMT2A with myeloid/lymphoid or mixed-lineage leukemia; translocated to 3 (MLLT3), also known as KMT2A-MLLT3, is particularly significant because it has been reported in more than 50% of pediatric and 25% of adult acute myeloid leukemia cases. The KMT2A-MLLT3 translocation creates the fusion protein that aberrantly recruits DOT1L (disruptor of telomeric silencing 1-like) and other chromatin-modifying enzymes to the HOXA9 locus, resulting in increased HOXA9 gene expression. HOXA9 expression disrupts normal hematopoietic differentiation and contributes to the development of mixed lineage leukemia by promoting the proliferation and survival of leukemic cells. My research focuses on unraveling the mechanisms that drive heightened DOT1L activity and its specific targeting to HOXA9, pivotal for the robust transcription observed in MLL. Our results showed that the HOXA cluster is marked by several active marks and chromatin modifying enzymes including H3K27ac, H3K4me3, H3K36me3, H3K79me2, DOT1L and DNase I. The heavy decoration by these active marks and proteins indicates that HOXA9 has an unstable chromatin structure, which reflects higher nucleosome turnover over the HOXA9 region. Higher turnover makes the chromatin more accessible to the transcriptional machinery, thereby increasing HOXA9 expression. Histone H3 has three forms: H3.1 and H3.2 as canonical, and H3.3 as a variant. The H3.3 variant can be more incorporated into nucleosomes with higher turnover, which can further enhance the transcription of the HOXA9 gene in MOLM 13 cells. Our results showed that the H3K79me2 level, which indicates DOT1L enzyme activity, is higher in MOLM-13 cells with the KMT2A-MLLT3 translocation. Several studies have shown that DOT1L activity depends on Histone H2B monoubiquitination at Lys 120 (H2BK120ub), a key modification in transcription elongation. Our results also revealed that the level of H2BK120ub is higher in MOLM-13 cells, which have increased DOT1L activity, suggesting a direct relationship between H2BK120ub and DOT1L activity in these cells. Bortezomib, an FDA-approved drug commonly used in clinical practice for multiple myeloma, was employed to investigate its effect on epigenetic marks involved in transcription elongation including the H3K79me2, H3K36me3, and H2BK120ub in MOLM-13 cells. Treatment with 5 nM bortezomib demonstrated significant reductions in H2BK120ub levels, H3K79me2, and HOXA9 gene expression in MLL. My findings underscore the critical role of H2BK120ub in regulating DOT1L methyltransferase activity and HOXA9 expression in MOLM-13 cells. These compelling results position bortezomib as a promising therapeutic avenue for treating MLL, offering new hope for patients affected by this challenging disease.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".