Activation of a nongenetic AHR-ELMSAN1 axis optimizes BET-targeting therapy and suppresses leukemia stem cells in preclinical models.

Developing strategies to enhance the response to bromodomain and extraterminal domain (BET) inhibitors and effectively eradicate cancer stem cells would represent a major cancer treatment advance against leukemia. Through a functional CRISPR screen, we identified the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, as a critical regulator of MYC expression and BET inhibitor sensitivity in human acute myeloid leukemia (AML). Constitutive or pharmacological activation of AHR repressed MYC and synergized with BET inhibitors to inhibit MYC transcription and suppress leukemia growth across diverse AML models.

Enforcement of stem-cell dormancy by nucleophosmin mutation is a critical determinant of unrestricted self-renewal during myeloid leukemogenesis.

Mutations in the NPM1 gene (NPMc+) and in the FLT3 gene (FLT3-ITD) represent the most frequent co-occurring mutations in acute myeloid leukemia (AML), yet the cellular and molecular mechanisms of their co-operation remain largely unexplored. Using mouse models that faithfully recapitulate human AML, we investigated the impact of these oncogenes on pre-leukemic and leukemic hematopoietic stem cells (HSC), both separately and in combination. While both NPMc+ and Flt3-ITD promote the proliferation of pre-leukemia HSC, only NPMc+ drives extended self-renewal by preventing the depletion of the quiescent HSC pool.

Epigenetic regulation of noncanonical menin targets modulates menin inhibitor response in acute myeloid leukemia.

Menin inhibitors that disrupt the menin-MLL interaction hold promise for treating specific acute myeloid leukemia (AML) subtypes, including those with KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncovered a potential resistance mechanism independent of canonical menin-MLL targets. We show that a group of noncanonical menin targets, which are bivalently cooccupied by active menin and repressive H2AK119ub marks, are typically downregulated after menin inhibition.

Adhesion Deregulation in Acute Myeloid Leukaemia.

Cell adhesion is a process through which cells interact with and attach to neighboring cells or matrix using specialized surface cell adhesion molecules (AMs). Adhesion plays an important role in normal haematopoiesis and in acute myeloid leukaemia (AML). AML blasts express many of the AMs identified on normal haematopoietic precursors.