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IKZF1 in leukemia and therapy response
localization and DNA binding activity.24,25 Sumoylation of IKZF1 on lysine residues occurs within the nucleus and seems to interfere with transcriptional repression.26,27 It was previously shown that IKZF1 is also subject to ubiq- uitination,20 and there is now renewed interest in this pathway, since both IKZF1 and IKZF3 are targets of the immunomodulatory drugs thalidomide, lenalidomide, pomalidomide and CC-122.28 These immunomodulatory drugs promote proteosomal degradation of IKZF1 and IKZF3 by redirecting the substrate specificity of the CRL4CRBN ubiquitin ligase complex.29,30 Immunomodulatory drugs show therapeutic effects in a broad range of hema- tologic malignancies through their ability to target the malignant cells and modulate the immune system and its microenvironment.
IKZF1 is essential for normal lymphopoiesis
Studies performed in both constitutive and conditional Ikzf1 knockout mouse models have demonstrated that IKZF1 function is not only required at different stages of lymphopoiesis,12,31,32 but also for normal myeloid, megakaryocyte and erythroid differentiation.33-36 Ikzf1- deficient mice (Ikzf1null/null) lack all B cells, natural killer cells, plasmacytoid dendritic cells and fetal T cells31,37 (Figure 2). Nonetheless, post-natal Ikzf1-null mice harbor early T lin- eage progenitors within the thymus and export mature T
cells to the periphery.38 Mice homozygous mutant for a hypomorphic allele of Ikzf1 (Ikzf1L/L) show reduced B-cell progenitors in the bone marrow compartment, but still generate normal counts of mature B2 cells.39 These splenic B cells display alterations in isotype selection during immunoglobulin class switch recombination and a hyper- proliferation phenotype upon antigenic stimulation.40,41 Although spontaneous progression to B-cell ALL is not observed in Ikzf1L/L mice, haplodeficient Ikzf1L/+ animals demonstrate an accelerated onset of B-cell leukemia in combination with a BCR-ABL1 transgene.42 Moreover, all Ikzf1L/L mice develop thymic lymphoma within a period of 10 months through activation of the Notch pathway.43 Ikzf1 mutant mice expressing dominant-negative isoforms of IKZF1 (Ikzf1DN/DN and Ikzf1Plstc/Plstc) demonstrate a wide- spread failure of hematopoiesis,44,45 highlighting the impor- tance of IKAROS transcription factors in hemato-lym- phoid differentiation. Notably, heterozygous Ikzf1 mutant mice develop T-cell malignancies with very high pene- trance and short latency in the case of the dominant-neg- ative isoforms,46,47 while this phenotype is less obvious in Ikzf1+/- mice.48
Detailed gene expression profiling has revealed that IKZF1 is essential for the generation of common lymphoid progenitors by priming lymphoid lineage-specific signa- tures in hematopoietic stem cells and lymphoid-primed
Figure 2. Summary of the observed phenotypes in the different constitutive Ikzf1 knockout mouse models. The knockout allele shows a schematic representation at which position the deletion or mutation is present in the mouse Ikzf1 gene. DN: dominant negative; Plstc: ENU-induced dominant-negative point mutation, called Plastic; Neo: neomycin gene; βGeo: fusion between LacZ and neomycin gene; ZF: zinc-finger; HSC: hematopoietic stem cell; NK: natural killer; pDCs: plasmacytoid dendritic cells; LT-HSC: long-term hematopoietic stem cell; GMPs: granulocyte-macrophage precursors; mo: months.
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