MECOM (MDS1 And EVI1 Complex Locus)

P1/2, N=52, Not yet recruiting, M.D. Anderson Cancer Center

Regulated in development and DNA damage response-1 (REDD1/DDIT4) is induced in response to environmental stress to restrain the mechanistic target of rapamycin complex 1 (mTORC1) signaling as an adaptive strategy to restore cellular homeostasis...Interestingly, RNA sequencing analysis reveals that the loss of the transcriptional regulator EVI-1/MECOM in cells deficient in REDD1/DDIT4 amplifies the ER stress-induced upregulation of TRAILR2/DR5, leading to enhanced apoptosis. In summary, our findings underscore the crucial role of REDD1/DDIT4 in regulating TRAILR2/DR5-induced caspase-8 activation and apoptosis under chronic ER stress, by inhibiting mTORC1 activity and promoting EVI-1/MECOM-mediated suppression of TRAILR2/DR5 gene expression.

P1, N=22, Recruiting, Richard Stone, MD | Trial completion date: Mar 2027 --> Mar 2028 | Trial primary completion date: Mar 2026 --> Mar 2027

Clinically, EVI1 overexpression is one of the most robust independent indicators of poor prognosis, associated with therapy resistance and reduced overall survival. This review provides a detailed discussion of the mechanisms underlying EVI1's activation, its complex molecular functions in hematopoietic transformation, and its profound clinical implications in hematological malignancies.

Moreover, SPINK2-deficient FUJIOKA cells revealed a significant association between SPINK2 and MECOM expression, consistent with findings in patients harbouring complex karyotypes, yet absent in other AML subsets from the TARGET-AML cohort. Our findings suggest a novel potential correlation between SPINK2 and MECOM expression in complex karyotype leukemias and warrant further investigation into the underlying molecular mechanisms through which the SPINK2-MECOM axis enforces aberrant self-renewal and the development of novel targeted approaches aimed at modulating its expression in complex karyotypic AML.

Study limitations include scRNA-seq restricted to the proliferative phase, which may limit generalizability. Nevertheless, future functional studies using primary epithelial organoids derived from EPs may provide a physiologically relevant model to evaluate targeted therapeutic strategies including hormonal interventions with potential applications in infertility management.

Compared to existing HMA/VEN-specific models, our model demonstrated superior low- vs. intermediate-risk discrimination (31.9-month separation, p=0.002; HR=0.45, p=0.003), with comparable C-index. Our model supports personalized risk stratification for HMA/VEN-treated AML, pending broader validation.

Collectively, these studies highlight a highly reproducible model of mutant ASXL1 in the appropriate cell context. Further, they are the first to functionally describe the mutant ASXL1 interactome in the context of the human HSC, identifying new dependencies with therapeutic potential.

Given the well-documented association between SF3B1 mutations and MECOM rearrangements, analysis of MECOM expression and RNA sequencing (RNA-seq) is crucial for SF3B1-mutated patients, even in the absence of elevated blast counts. Furthermore, this case underscores the need for further research into the synergistic biological role of spliceosome mutations and MECOM rearrangements in driving leukemia.

LSPC-Cycle, FLT3-ITD and NUP98::KDM5A were considered independent prognostic factors in multivariate analysis. Findings indicate the prognostic relevance of cellular hierarchy and the importance of integrating hierarchy-specific molecular profiles for improved risk stratification and treatment formulation.

In AML with 3q26.2 rearrangements (r) the distal GATA2 hematopoietic enhancer becomes aberrantly relocated leading to activation of EVI1 expression. In patient-derived xenograft (PDX) models of AML with MECOM-r, compared to each drug alone, co-treatment with FHD-286 and BETi OTX015 significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as promising therapy of AML with chromosome 3q26.2 rearrangement and EVI1 overexpression.

In prostate cancer, MECOM was exclusively overexpressed in both CRPC and enzalutamide-resistant CRPC and interacted with AR in the nucleus...These insights reveal the crucial role of EVI1 in regulating cell survival within the context of an AR-reprogrammed chromatin landscape. More importantly, the findings suggest that MECOM overexpression may be another biomarker that could significantly broaden the use of PARP inhibitors beyond those with HRR gene mutations.