Ikaros: Exploiting and targeting the hematopoietic stem cell niche in B-progenitor acute lymphoblastic leukemia  Michelle L. Churchman, Charles G. Mullighan 

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Ikaros: Exploiting and targeting the hematopoietic stem cell niche in B-progenitor acute lymphoblastic leukemia  Michelle L. Churchman, Charles G. Mullighan  Experimental Hematology  Volume 46, Pages 1-8 (February 2017) DOI: 10.1016/j.exphem.2016.11.002 Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 1 Ikaros architecture and effects of perturbation. (A) Ikaros protein structure comprised of coding exons 2 through 8, including four N-terminal zinc fingers that comprise the DNA-binding domain and two C-terminal zinc fingers that are responsible for hetero- and homodimerization. (B) Immunofluorescence using an N-terminal specific anti-Ikaros antibody (green) and a DNA-binding stain, 4′,6-diamidino-2-phenylindole (DAPI; blue) showing punctate, nuclear staining of endogenous Ikaros in primary mouse Arf–/– BCR-ABL1+ pre-B cells transduced with empty vector (left panel) or IK6 (right panel, which lacks the DNA-binding domain and grossly mislocalizes to the cytoplasm. Scale bar indicates 5 μm. (C) Schematic of Ikaros dimerization, DNA binding, and association with the NuRD complex to repress the transcription of adhesion molecules and genes that restrict differentiation to allow proper developmental progression of lymphoid progenitors (top). This causes a loss of DNA-binding capability with the retention of the ability to dimerize and results in potent dominant-negative effects of IK6, resulting in inappropriate expression of genes that affect a block in differentiation and confer an adhesive phenotype to typically nonadherent lymphoid progenitors. (D) Schematic summary of the effects of Ikaros alterations in various engineered mouse models of BCR-ABL1+ B-ALL in vivo. Transduction of BCR-ABL1 into non-manipulated whole bone marrow of Ikzf1+/− or wild-type mice and transplantation directly back into syngeneic wild-type mice results in marked acceleration of B-ALL in an Ikzf1+/− background (left arm). IK6 cooperates with Arf loss in driving lymphoid leukemia, as demonstrated by transduction and transplantation of lineage-negative bone marrow cells from either wild-type Arf−/− mice with BCR-ABL1 and empty vector or IK6 (middle arm). BCR-ABL1-transformed pre-B cells from the indicated genotypes in combination with IK6 have varying degrees of sensitivity to tyrosine kinase inhibition with dasatinib (right arm). Experimental Hematology 2017 46, 1-8DOI: (10.1016/j.exphem.2016.11.002) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 1 Ikaros architecture and effects of perturbation. (A) Ikaros protein structure comprised of coding exons 2 through 8, including four N-terminal zinc fingers that comprise the DNA-binding domain and two C-terminal zinc fingers that are responsible for hetero- and homodimerization. (B) Immunofluorescence using an N-terminal specific anti-Ikaros antibody (green) and a DNA-binding stain, 4′,6-diamidino-2-phenylindole (DAPI; blue) showing punctate, nuclear staining of endogenous Ikaros in primary mouse Arf–/– BCR-ABL1+ pre-B cells transduced with empty vector (left panel) or IK6 (right panel, which lacks the DNA-binding domain and grossly mislocalizes to the cytoplasm. Scale bar indicates 5 μm. (C) Schematic of Ikaros dimerization, DNA binding, and association with the NuRD complex to repress the transcription of adhesion molecules and genes that restrict differentiation to allow proper developmental progression of lymphoid progenitors (top). This causes a loss of DNA-binding capability with the retention of the ability to dimerize and results in potent dominant-negative effects of IK6, resulting in inappropriate expression of genes that affect a block in differentiation and confer an adhesive phenotype to typically nonadherent lymphoid progenitors. (D) Schematic summary of the effects of Ikaros alterations in various engineered mouse models of BCR-ABL1+ B-ALL in vivo. Transduction of BCR-ABL1 into non-manipulated whole bone marrow of Ikzf1+/− or wild-type mice and transplantation directly back into syngeneic wild-type mice results in marked acceleration of B-ALL in an Ikzf1+/− background (left arm). IK6 cooperates with Arf loss in driving lymphoid leukemia, as demonstrated by transduction and transplantation of lineage-negative bone marrow cells from either wild-type Arf−/− mice with BCR-ABL1 and empty vector or IK6 (middle arm). BCR-ABL1-transformed pre-B cells from the indicated genotypes in combination with IK6 have varying degrees of sensitivity to tyrosine kinase inhibition with dasatinib (right arm). Experimental Hematology 2017 46, 1-8DOI: (10.1016/j.exphem.2016.11.002) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 2 Targetable pathways in Ikaros-altered leukemic cells affecting cell-to-cell and cell-to-stroma interactions within the bone marrow niche. Shown is an overview of key signaling molecules aberrantly upregulated in IKZF1-deficient leukemic B-ALL cells that mediate cell adhesion, survival, cytoskeletal reorganization, and migration. Integrin signaling can be activated by interactions with the extracellular matrix or cell-to-cell interactions via binding of THY1 at the cell surface. L-selectin (SELL) plays a role in tethering and rolling of lymphocytes along endothelial cells of the vasculature. FAK activation is central to many processes that promote adhesion, migration, proliferation, and survival, thus providing an amenable therapeutic target for inhibition. In BCR-ABL1 ALL, FAK is activated by integrin signaling and BCR-ABL1-mediated Src activation. Together, aberrant overexpression of these signaling molecules and activation of their signaling pathways results in leukemic cells that are poised to extravasate, infiltrate, and adhere to the extravascular HSC niche. These pathways can be attenuated by rexinoid receptor agonists, which upregulate Ikaros expression directly in leukemic cells that retain an intact wild-type IKZF1 allele. In leukemic cells lacking functional Ikaros, it is important to note that rexinoids can also induce broad changes in expression in an IKZF1-independent manner to induce differentiation, thereby providing another attractive therapeutic intervention for refractory B-ALL. Experimental Hematology 2017 46, 1-8DOI: (10.1016/j.exphem.2016.11.002) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions