Gindin, T. | Search bioRxiv

bioRxiv2025

Hi-C for genome-wide detection of enhancer-hijacking rearrangements in routine lymphoid cancer biopsies

Standard techniques for detecting genomic rearrangements in formalin-fixed paraffin-embedded (FFPE) biopsies have important limitations. We performed FFPE-compatible Hi-C on 44 clinical biopsies comprising large B-cell lymphomas (n=18), plasma cell neoplasms (n=14), and other diverse lymphoid cancers, identifying consistent topological differences between malignant B cell and plasma cell states. Hi-C detected expected oncogene rearrangements at high concordance with fluorescence in-situ hybridization (FISH) and supported enhancer-hijacking in recurrent rearrangements of BCL2, CCND1, and MYC, plus unanticipated variants involving homologous loci. Hi-C identified unanticipated non-coding rearrangements involving PD-1 ligand genes and other loci of potential therapeutic relevance, distinguished between functionally divergent classes of BCL6 rearrangements, and provided topological information supporting the interpretation of atypical MYC rearrangements. In biopsies lacking MYC-activating rearrangements, Hi-C revealed differential interactions with functionally-validated disease-specific native MYC locus enhancers. FFPE-compatible Hi-C detects oncogene rearrangements and their topological consequences at genome-wide scale, finding clinically-relevant drivers that are missed by standard approaches.

genomics↗

bioRxiv2017

Peptidomimetic blockade of MYB in acute myeloid leukemia

Aberrant gene expression is a hallmark of acute leukemias. However, therapeutic strategies for its blockade are generally lacking, largely due to the pharmacologic challenges of drugging transcription factors. MYB-driven gene trans-activation with CREB-binding protein (CBP)/P300 is required for the initiation and maintenance of a variety of acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a prototypical peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYB:CBP/P300 complex at micromolar concentrations and rapidly accumulates in the nuclei of AML cells. We found that treatment of AML cells with MYBMIM, led to the displacement of the MYB:CBP/P300 complex in cells, displacement of MYB from oncogenic enhancers and promoters enriched for MYB binding sites, and downregulation of MYB-dependent gene expression, including of MYC and BCL2 oncogenes. Both human MLL-rearranged and non-rearranged AML cells, underwent mitochondrial apoptosis in response to MYBMIM treatment, which could be partially rescued by ectopic expression of BCL2. We observed that MYBMIM treatment impeded leukemia growth and extended survival of immunodeficient mice engrafted with primary patient-derived MLL-rearranged leukemia cells. These findings emphasize the exquisite dependence of human AML on MYB:CBP/P300 transcriptional dysregulation, and establish a pharmacologic approach for its therapeutic blockade.

cancer biology↗