The XPO1-FOXC1-HOX Functional Axis Opens New Therapeutic Avenues to Treat DEK-NUP214 AML Patients
Bibliographic record
Abstract
Introduction: t(6;9)(p23;q34.1)/DEK-NUP214 patients represent a discrete group of younger AML patients recognised as a separate disease entity in the World Health Organization classification of myeloid neoplasms. They typically display a dismal prognosis, higher relapse rate and a striking co-occurrence with FLT3-ITD mutations in > 70% of cases. DEK is a nuclear factor that has been attributed multifunctional roles, including gene regulation, while its fusion partner, NUP214, plays a pivotal role in nuclear export by interacting with transport receptors such as XPO1. However, the precise mechanism by which DEK-NUP214 drives leukaemia remains unclear. Aims: Application of a multi-omics profiling to understand the oncogenic mechanisms underlying DEK-NUP214 fusion protein and identify potential therapeutical vulnerabilities. Methods: A comprehensive multi-omics screening (whole genome sequencing, targeted sequencing, transcriptomics, (phosphor)proteomics, mass cytometry (CyTOF) and in vitro drug screening) was conducted on 57 untreated primary AML samples from cytogenetically poor-risk AML, including four cases with t(6;9) translocation (complex karyotype (n=20), -7/del(7) (n=15), KMT2A rearrangements (not including t(9;11)) (n=12), t(6;9) (n=4) and other poor-risk karyotypes (inv(3), -5/del(5), t(3;12)/+8 or -17/del(17)) (n=6)). The t(6;9)/DEK-NUP214 cell line FKH-1, was utilised as a model for in vitro experiments and compared with other AML cell lines (OCI-AML3, KASUMI-1, THP-1, P31-FUJ, MV4-11 and K562). In vitro drug treatments were conducted in the cell lines and patient samples using Cell-Titer&Glo, and transcriptional changes were evaluated using qPCR and RNA-seq. To examine the function of selected target genes of DEK-NUP214, we used lentiviral shRNA system followed by cell cycle, apoptosis, differentiation, and cell proliferation assays. Results: An integrative RNA-seq analysis of our cohort and a separate series of 691 AML cases that included three additional t(6;9) cases (Leucegene, https://leucegene.ca/) revealed 128 genes significantly upregulated and 74 downregulated in t(6;9) patients compared to other AML samples. The overexpressed genes included some known leukaemia mediators (FOXC1, HOXA and HOXB genes), the genes previously reported in t(6;9) patients (EYA3, SESN1 and PRDM2) and novel genes with roles in haematopoiesis or cancer cell survival that showed the most significant differences (NFIX and GGT5). The significant overexpression of these genes was also confirmed in the t(6;9) FKH-1 cell line. In vitro drug screening of 527 licenced or investigational drugs allowed us to identify the compounds that were most effective and selective for t(6;9) patients in comparison with other AML cytogenetic groups. The two XPO1 inhibitors (Selinexor and Eltanexor) included in our drug panel were within the four top-ranked compounds. Of note, qPCR and RNA-seq analyses in the cell lines and primary patient samples showed that inhibition of XPO1 resulted in significant downregulation of the expression of FOXC1, NFIX, EYA3, HOXA and HOXB genes, highlighting a functional axis linking these target genes, XPO1 and the fusion. In line with this finding, silencing of FOXC1 in the FKH-1 cells led to an increase in apoptosis, lower cell proliferation and reduced clonogenic capacity, accompanied by a concomitant downregulation of HOXA and HOXB genes. Collectively, these findings support a key role of FOXC1 in DEK-NUP214-driven AML. Conclusion: This study offers valuable insights into the molecular and pathological mechanisms underlying t(6;9)-AML, revealing a functional interaction between DEK-NUP214, XPO1 and FOXC1, and providing evidence to consider XPO1 inhibition as a potential new avenue to treat these patients.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".