SummaryPharmacologic inhibition of LSD1 promotes blast cell differentiation in acute myeloid leukemia (AML) with MLL translocations. The assumption has been that differentiation is induced through blockade of LSD1’s histone demethylase activity. However, we observed that rapid, extensive, drug-induced changes in transcription occurred without genome-wide accumulation of the histone modifications targeted for demethylation by LSD1 at sites of LSD1 binding and that a demethylase-defective mutant rescued LSD1 knockdown AML cells as efficiently as wild-type protein. Rather, LSD1 inhibitors disrupt the interaction of LSD1 and RCOR1 with the SNAG-domain transcription repressor GFI1, which is bound to a discrete set of enhancers located close to transcription factor genes that regulate myeloid differentiation. Physical separation of LSD1/RCOR1 from GFI1 is required for drug-induced differentiation. The consequent inactivation of GFI1 leads to increased enhancer histone acetylation within hours, which directly correlates with the upregulation of nearby subordinate genes.

Highlights d NK cells drive broad inflammatory remodeling characteristic of T-cell-inflamed tumors d PGE2 acting on EP2 and EP4 on NK cells prevents the TME switch enabling immune escape d Opposing inflammatory profiles found in many human cancer types have prognostic value d A signature capturing pro-and anti-tumor factors predicts response to immunotherapy

New results are presented for Ps(1s) scattering by H(1s), He(1 1 S) and Li(2s). Calculations have been performed in a coupled state framework, usually employing pseudostates, and allowing for excitation of both the Ps and the atom. In the Ps(1s)-H(1s) calculations the H − formation channel has also been included using a highly accurate H − wave function. Resonances resulting from unstable states in which the positron orbits H − have been calculated and analysed. The new Ps(1s)-He(1 1 S) calculations still fail to resolve existing discrepancies between theory and experiment at very low energies. The possible importance of the Ps − formation channel in all three collision systems is discussed.