TEXT
Since the discovery of the Ikaros gene, less than 20 years ago, there has been tremendous advance in understanding the function of this gene and its protein products at the molecular, cellular, and biological levels, and in elucidating the clinical significance of these findings. The first published papers identified Ikaros as a master regulator of hematopoiesis, and in particular a gene essential for lymphocyte development[1]. Advanced biochemical studies revealed that Ikaros binds DNA and regulates its target genes via chromatin remodeling[2]. These discoveries helped in understanding Ikaros function at both the biochemical and cellular levels and advanced our general knowledge of the mechanisms by which transcription factors control gene expression. Extensive association studies that examined the consequences of the loss of Ikaros function due to deletions, to mutations, or to overexpression of dominant negative isoforms, established that Ikaros acts as a tumor suppressor in acute lymphoblastic leukemia and possibly in other types of hematological malignancies[3-5]. The discovery of multiple signal transduction pathways that regulate Ikaros function identified signaling networks that are involved in normal and malignant hematopoiesis. These findings provided a mechanistic rationale for inhibition of these pathways as a component of treatment for hematological malignancies[6,7]. In this Topic Highlight series, we have assembled a group of international experts to provide an update on the progress in understanding the role of Ikaros in normal hematopoiesis, immune regulation, and leukemia, and to provide insights into the cellular and biochemical function of Ikaros.
The first two papers in this series provide in-depth reports on the role of Ikaros in different types of leukemia. The first review concentrates on the role of Ikaros in T-cell leukemia[8]. The association of the loss of Ikaros activity and the development of T cell leukemia in mice and in humans is discussed. Authors present evidence that deletion of Ikaros is less frequent in T-cell acute lymphocytic leukemia (ALL) than B-cell ALL in humans. They discuss the possible downstream pathways that are controlled by Ikaros and whose deregulation contributes to leukemogenesis. The review by Greif et al[9] focuses on the role of Ikaros as a regulator of cell proliferation in myeloid leukemia. The authors discuss the alteration of Ikaros function in CALM/AF10 positive acute myeloid leukemia (AML), as well as in chronic myeloid leukemia (CML). The models presented describe how the alteration of Ikaros function by CALM/AF10 accounts for impaired thymocyte differentiation and AML with lymphoid characteristics, in addition to providing insights into the role of Ikaros in regulating pre-B-cell receptor signaling.
The next three reports provide an overview of the role of Ikaros in B cell development, myeloid differentiation, and immune function. It has been hypothesized that Ikaros regulates B cell development at multiple levels. Sellars et al[10] systematically summarize the current knowledge of Ikaros function in this process. They outline three roles for Ikaros in B cell development: (1) control of B lineage commitment; (2) regulation of the pro-B to pre-B cell transition through regulation of immunoglobulin (Ig) gene recombination via activation of the Rag1 and Rag2 genes; and (3) regulation of pre-BCR signaling by repressing transcription of the λ5 gene. The second part of this detailed review describes Ikaros’ role in the regulation of B cell activation and isotype selection during immunoglobulin class switch recombination. In the next review, Francis et al[11] focus on the role of Ikaros as a regulator of normal myeloid differentiation and function. Authors emphasize Ikaros function in myeloid lineage commitment in the classic and lymphoid-myeloid progenitor hematopoietic pathways. The potential of Ikaros involvement in regulating expression of the Gr-1 gene, as well as inducible nitric oxide synthase in macrophages is reviewed. The role of the myeloid-specific Ikaros isoform, Ik-x in myeloid differentiation is discussed. The interesting role of Ikaros in regulating the activity of vasoactive intestinal peptide in human CD4+ lymphocytes is nicely presented by Dorsam et al[12]. The authors review the current evidence that Ikaros directly regulates the expression of vasoactive intestinal peptide receptor-1 (VPAC1) in T lymphocytes. The significance of Ikaros-controlled regulation of VPAC1 expression as a potential pathway by which the nervous system regulates immune response is discussed.
The last three reviews provide insights into the molecular mechanisms that regulate Ikaros activity and structural determinants of Ikaros function. Li et al[13] provide an in-depth review of the functional significance of the two largest human Ikaros isoforms - IK-1 and IK-H. The authors describe data demonstrating that coordinated expression of IK-1 and IK-H regulates Ikaros DNA binding, pericentromeric localization, and chromatin remodeling. The evidence that forms the basis of the current hypothesis - that the presence of the IK-H isoform determines whether Ikaros complexes function as activators or repressors of gene transcription - is discussed. The role of two signal transduction pathways in the regulation of Ikaros function is described by Song et al[14]. The authors summarize the evidence that phosphorylation by casein kinase 2 and dephosphorylation by protein phosphatase 1 directly regulates the activity of Ikaros protein. The control of Ikaros’ DNA-binding affinity and subcellular localization, as well as its degradation via the ubiquitin pathway by two opposing signal transduction pathways is described. The role of Ikaros phosphorylation in T cell differentiation and regulation of target gene expression has been emphasized. A model by which the phosphorylation of Ikaros regulates its tumor suppressor activity and controls malignant transformation is outlined. Finally, Payne[15] presents an excellent review of the structural aspects of zinc finger motifs present in the Ikaros protein and uses knowledge of zinc finger structure to explain their significance in Ikaros function. In this review, the structure of DNA-binding N-terminal zinc fingers, as well as protein-interacting C-terminal zinc fingers is outlined. Based on detailed analysis, the author proposes an interesting hypothesis that the fourth N-terminal zinc finger serves the dual function of promoting DNA binding and participating in the formation of ternary complexes of Ikaros dimers with DNA.
The present Topic Highlight series “The role of Ikaros in hematopoiesis and leukemia” does not contain a complete reference of all experimental data regarding the activity of Ikaros in these processes. It represents a summary of current knowledge of the function of Ikaros in normal hematopoiesis and in hematopoietic malignancy. These reviews provide a foundation for future studies that will be aimed at validating some of the proposed models and advancing our understanding of hematopoiesis and leukemogenesis.
