The Combined Expression Patterns of Ikaros Isoforms Characterize Different Hematological Tumor Subtypes

Orozco, Carlos; Acevedo, Andrés; Cortina, Lázaro; Cuellar, Gina; Duarte, Mónica; Martin, Liliana; Mesa, Néstor M.; Muñoz, Javier; Portilla, Carlos Andres; Quijano, Sandra; Quintero, Guillermo; Rodríguez, Martín González; Saavedra, Carlos; Groot, Helena; Torres, María Mercedes; López-Segura, Valeriano

doi:10.1371/journal.pone.0082411

Cited by 7 publications

(5 citation statements)

References 35 publications

(35 reference statements)

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“…In this context, recent papers described the capability of IMiDs to induce CRBN-dependent degradation of the Ikaros family zinc finger protein-1 (IKZF1, Ikaros) and 3 (IKZF3, Aiolos) [ 34 , 35 ], two transcription factors involved in lymphoid development and differentiation and highly expressed in B cell malignancies, including MM [ 36 , 37 ]. Loss of these proteins was shown to mediate important therapeutic activities of IMiDs, such as increased IL-2 production by T cells [ 35 , 38 ] or anti-proliferative effects in MM cells [ 34 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma

et al. 2015

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Immunomodulatory drugs (IMiDs) have potent anti-tumor activities in multiple myeloma (MM) and are able to enhance the cytotoxic function of natural killer (NK) cells, important effectors of the immune response against MM. Here, we show that these drugs can enhance the expression of the NKG2D and DNAM-1 activating receptor ligands MICA and PVR/CD155 in human MM cell lines and primary malignant plasma cells. Depletion of cereblon (CRBN) by shRNA interference strongly impaired upregulation of these ligands and, more interestingly, IMiDs/CRBN-mediated downregulation of the transcription factors Ikaros (IKZF1), Aiolos (IKZF3) and IRF4 was critical for these regulatory mechanisms. Indeed, shRNA knockdown of IKZF1 or IKZF3 expression was both necessary and sufficient for the upregulation of MICA and PVR/CD155 expression, suggesting that these transcription factors can repress these genes; accordingly, the direct interaction and the negative role of IKZF1 and IKZF3 proteins on MICA and PVR/CD155 promoters were demonstrated. Finally, MICA expression was enhanced in IRF4-silenced cells, indicating a specific suppressive role of this transcription factor on MICA gene expression in MM cells.Taken together, these findings describe novel molecular pathways involved in the regulation of MICA and PVR/CD155 gene expression and identify the transcription factors IKZF-1/IKZF-3 and IRF4 as repressors of these genes in MM cells.

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Section: Introductionmentioning

confidence: 99%

The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma

et al. 2015

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“…This binding prevents the CRBN auto-ubiquitination and also promotes the recognition and degradation of the transcription factors Ikaros and Aiolos. Ikaros and Aiolos are critical for B and T cell biology [78][79][80].…”

Section: Immunomodulatory Drugsmentioning

confidence: 99%

Magic pills: new oral drugs to treat chronic lymphocytic leukemia

Vitale

Griggio

Todaro

et al. 2017

Expert Opinion on Pharmacotherapy

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Introduction: A deeper understanding of chronic lymphocytic leukemia (CLL) biology has led to the identification of new promising therapeutic targets. Different classes of molecules are currently under investigation and novel oral drugs have recently been approved or are in a late stage of clinical development. Areas covered: We present biological data illustrating the heterogeneous mechanisms of action of new oral drugs in CLL. Moreover, we provide clinical data from phase I to III studies, and discuss efficacy and side effects profile of these new therapies. Data are derived from peer-reviewed articles indexed in PubMed and from abstracts presented at major international meetings. Expert opinion: Novel oral drugs represent a valuable alternative to chemo-immunotherapy for patients with CLL, especially when high-risk disease features are present and when age or comorbidities preclude the use of standard treatments. Based on data from ongoing clinical trials, the indications of already approved agents will most likely be expanded and new options will soon be available. Moreover, treatment combinations will broaden the therapeutic armamentarium of physicians treating CLL. The availability of multiple choices is of benefit for patients with CLL, but also represents a challenge for the need of choosing the right drug for each patient. ARTICLE HISTORY

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“…The first four zinc-fingers represent a DNA-binding domain (DBD) whereas the last two zinc-fingers are components of a dimerization domain; the latter allows competitive binding between isoforms. 8 These domains are encoded by seven different exons, and differential splicing generates different isoforms. Ikaros isoforms that display at least three zinc-fingers in the DBD are considered dominant positive (DP, IK1-3), whereas Ikaros isoforms with less than three zinc-fingers in the DBD are considered dominant negative (DN, IK4-9).…”

Section: Introductionmentioning

confidence: 99%

Regulation of PI3K signaling in T-cell acute lymphoblastic leukemia: a novel PTEN/Ikaros/miR-26b mechanism reveals a critical targetable role for PIK3CD

et al. 2017

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, and T-ALL patients are prone to early disease relapse and suffer from poor outcomes. The PTEN, PI3K/AKT, and Notch pathways are frequently altered in T-ALL. PTEN is a tumor suppressor that inactivates the PI3K pathway. We profiled miRNAs in Pten-deficient mouse T-ALL and identified miR-26b as a potentially dysregulated gene. We validated decreased expression levels of miR-26b in mouse and human T-ALL cells. In addition, expression of exogenous miR-26b reduced proliferation and promoted apoptosis of T-ALL cells in vitro, and hindered progression of T-ALL in vivo. Furthermore, miR-26b inhibited the PI3K/AKT pathway by directly targeting PIK3CD, the gene encoding PI3Kδ, in human T-ALL cell lines. ShRNA for PIK3CD and CAL-101, a PIK3CD inhibitor, reduced the growth and increased apoptosis of T-ALL cells. Finally, we showed that PTEN induced miR-26b expression by regulating the differential expression of Ikaros isoforms that are transcriptional regulators of miR-26b. These results suggest that miR-26b functions as a tumor suppressor in the development of T-ALL. Further characterization of targets and regulators of miR-26b may be promising for the development of novel therapies.

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The Combined Expression Patterns of Ikaros Isoforms Characterize Different Hematological Tumor Subtypes

Cited by 7 publications

References 35 publications

The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma

The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma

Magic pills: new oral drugs to treat chronic lymphocytic leukemia

Regulation of PI3K signaling in T-cell acute lymphoblastic leukemia: a novel PTEN/Ikaros/miR-26b mechanism reveals a critical targetable role for PIK3CD

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