Ikaros regulation: study on hemo-lymphopoiesis

Massachusetts General Hospital, Boston MA

Investigators

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Abstract

Abstract We test the hypothesis that IKAROS establishes chromatin configurations and spatial organization that support lymphoid lineage priming while it maintains and refines these configurations to effect later cell fate restrictions and ultimately provide proper effector cell function. In Aim 1, we study the mechanisms of lineage priming and commitment, as HSCs and multipotent progenitors traverse functionally distinct differentiation pathways. We characterize early developmental trajectories based on chromatin accessibility and gene expression at the single cell level and test how these are influenced by IKAROS. Regulatory elements and networks of transcription factors (TFs) that operate through these genomic sites are identified and validated by complementary chromatin-based approaches that also examine how chromatin activity of these elements and factors is influenced by IKAROS. We evaluate the contribution of IKAROS- collaborating or -competing factors to the loss-of-IKAROS phenotypes. We finally examine how 3D genome organization is controlled by IKAROS at the root of the hemo-lymphoid system. In Aim 2, we focus on how progenitor plasticity is controlled by establishing and maintaining lineage-appropriate epigenomic configurations and whether these can be fully restored after disruption. We exploit a newly developed mAID-IKAROS/OsTIR to study the order of events on chromatin disruption and re-organization. We examine whether duration of the mutant state imposes temporal constraints on successful restoration of wild type behavior. We test IKAROS’ role in retrograde differentiation from immature B to small pre-B cells for receptor editing. We examine the effects of acute IKAROS depletion in vivo over a broad spectrum of the hematopoietic lineage, with a focus on cells responsible for long-term maintenance. We then directly compare the effects of this highly specific depletion of IKAROS to IMID drugs used to deplete IKAROS family members to treat hematopoietic malignancies using humanized Cereblon mouse models. Successful completion of this work provides fundamental knowledge about how the genome is configured to support orderly development within a lineage. It has actionable implications for efforts to treat human diseases caused or exacerbated by IKAROS loss (BALL), sustained by IKAROS activity (MM), or where efforts to harness cells for immunotherapy are impacted by IKAROS-regulated effector state transitions.