Transcriptional circuits in B cell transformation

Abstract

Loss of IKAROS in committed B cell precursors causes a block in differentiation while at the same time augments aberrant cellular properties, such as bone marrow stromal adhesion, self-renewal and resistance to glucocorticoid-mediated cell death. B cell acute lymphoblastic leukemias originating from these early stages of B cell differentiation and associated with IKAROS mutations share a high-risk cellular phenotype suggesting that deregulation of IKAROS-based mechanisms causes a highly malignant disease process. Recent studies show that IKAROS is critical for the activity of super-enhancers at genes required for pre-BCR signaling and differentiation, working either downstream of or in parallel with B cell master regulators such as EBF1 and PAX5. IKAROS also directly represses a cryptic regulatory network of transcription factors prevalent in mesenchymal and epithelial precursors that includes YAP1, TEAD1/2, LHX2 and LMO2, and their targets, which are not normally expressed in lymphocytes. IKAROS prevents not only expression of these “extra-lineage” transcription factors but also their co-operation with endogenous B cell master regulators, such as EBF1 and PAX5, leading to the formation of a de novo for lymphocytes super-enhancer network. IKAROS coordinates with the Polycomb repression complex (PRC2) to provide stable repression of associated genes during B cell development. However, induction of regulatory factors normally repressed by IKAROS starts a feed-forward loop that activates de novo enhancers and elevates them to super-enhancer status, thereby diminishing PRC2 repression and awakening aberrant epithelial-like cell properties in B cell precursors. Insight into IKAROS-based transcriptional circuits sets new paradigms for cell differentiation but also provides new approaches for classifying and treating high-risk human B-ALL that originates from these early stages of B cell differentiation

The Current Genomic and Molecular Landscape of Philadelphia-like Acute Lymphoblastic Leukemia

“…It has recently been implicated as an epigenetic regulator [36] with the ability to induce active enhancers and 4 of 17 super-enhancers [37]. IKAROS plays key roles in hematopoiesis and lymphopoiesis [38,39] and is of importance for B-ALL as it is essential for the differentiation of B cell precursors [40].…”

“…Although the extent of IKAROS tumor suppressor mechanisms are unclear, it has been shown to bind DNA and regulate the expression of genes involved in cellular proliferation [43]. Further, the loss of IKAROS regulatory activity in B cell precursors is believed to contribute to the block in B cell differentiation that is characteristic of B-ALL cells [40]. IKZF1 deletion also contributes to chemoresistance in the leukemic cells [12].…”

Human dendritic cell immunodeficiencies

“…pDC deficiency with expansion of cDC1 and reduced non-classical monocytes is an additional cellular phenotype invariably associated with this mutation [101]. IKZF1 is critical for the activity of super-enhancers at genes required for pre-B cell receptor signaling and differentiation, working with B cell master regulators including EBF1 and PAX5 [102]. Targets of IKZF1, identified by CHIP-Seq [103], include ID2, suppression of which is necessary for pDC development and BATF3, required for cDC1 terminal differentiation.…”

Loss of the FOXP1 Transcription Factor Leads to Deregulation of B Lymphocyte Development and Function at Multiple Stages

“…4A, 4B). In scanning the literature, we found a number of examples of T2 disruption [reviewed previously (70); but none without disruption of stages downstream].…”