PF208 MN1 IS INDISPENSABLE FOR MLL‐REARRANGED ACUTE MYELOID LEUKEMIA
Bibliographic record
Abstract
Background: Mixed lineage leukemia ( MLL/KMT2A ) rearrangements (MLL‐r) are one of the most frequent chromosomal aberrations in AML. In addition, Meningioma 1 (MN1) expression serves as a prognostically important factor in AML patients being associated with poor prognosis. Overexpression of MN1 induces AML in mice and causes resistance to cytarabine and all‐trans‐retinoic acid (ATRA) induced cytotoxic/differentiation effects. Aims: To evaluate the function of MN1, a cofactor of HOXA9 and MEIS1, in human and murine AML cells by CRISPR‐Cas9 mediated deletion of MN1. Methods: MN1 was deleted in murine cells transformed by MLL‐AF9/HOXA9/HOXA9MEIS1/E2A‐HLF and 10 human leukemia cell lines (THP‐1, MV4–11, NB4, OCI‐AML2, OCI‐AML3, U937, K562, Kasumi‐1, HL‐60 and HEL). Murine and human leukemic models with engineered deletion of MN1 were studied as single cell clones and were characterized in vitro and in vivo . Results: Out of 96 to 288 CRISPR‐Cas9‐MN1‐transduced single sorted clones per cell line, 30 percent of them proliferated and only 0 to 8.9% of them were found to have a MN1‐deletion. Interestingly, only 1 MN1‐deleted clone was obtained from four different murine cell lines with HOX‐dependent oncogene expression suggesting that MN1 loss impairs clonogenicity of MLL‐r and HOXA9‐transformed cells. Loss of MN1 reduced in vitro proliferation and impaired colony‐forming potential up to 22‐fold in MLL‐r murine and human leukemia cells. MN1 deletion also suppressed cell cycle, promoted apoptosis and induced differentiation in MLL positive leukemia cells. MN1 was critically required for in vivo leukemogenicity of MLL‐AF9 murine leukemic cells. Mice transplanted with MLL‐AF9/Mn1null cells had <1% engraftment in all ten mice, whereas mice transplanted with MLL‐AF9/Mn1 wt cells showed >90% engraftment at 4 weeks with high WBC counts. Loss of Mn1 significantly prolonged survival of mice transplanted with MLL‐AF9/Mn1null cells as compared to mice transplanted with MLL‐AF9/Mn1 wt cells (median survival of 35 days). Additionally, we transplanted MN1 wildtype or MN1null cells of THP‐1 and MV‐4‐11 subcutaneously in NOD‐SCID mice and monitored tumor formation. Deletion of MN1 led to significantly reduced tumor volumes in both THP‐1 and MV‐4‐11 cells (MN1null) as compared to their MN1 wild type control. ChIP sequencing and gene expression analysis suggested that MN1 is required in MLL‐r leukemias to maintain expression of the distal Hoxa cluster and Meis1 and as a cofactor of the Hoxa9/Meis1 transcriptional complex and their target genes essential for leukemogenic activity. Also, we treated CD34+ cells from healthy donors and MLL‐AF9 positive AML cells with control/anti‐MN1 siRNA. MN1 expression was found to be critical for proliferation of MLL‐transformed leukemic cells while it had no effect on CD34+ cells from healthy donors, proposing MN1 as a therapeutic target in MLL‐transformed AML. Summary/Conclusion: Our study offers insight to the function of endogenous MN1 expression in leukemogenesis of MLL‐r AML. Our data shows that MN1 is essential for MLL fusion leukemias via regulation of Hoxa cluster and Meis genes and serves as a therapeutic target in MLL‐r AML.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.011 | 0.005 |
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; both teacher heads agree on what is shown here.
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".