Ikaros mediates gene silencing in T cells through Polycomb repressive complex 2

Oravecz, Attila; Apostolov, Apostol; Polak, Katarzyna; Jost, Bernard; Gras, Stéphanie Le; Chan, Susan; Kastner, Philippe

doi:10.1038/ncomms9823

Cited by 61 publications

(72 citation statements)

References 58 publications

(92 reference statements)

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“…IKAROS is involved in maintaining PRC2 activity at these gene loci in either a direct or indirect manner. A direct IKAROS association with PRC2 and targeting of this complex were reported in T-cell precursors (Oravecz et al 2015). However, we failed to detect a direct association between IKAROS and the PRC2 complex by immunoprecipitation in B-cell precursors (data not shown).…”

Section: Discussionmentioning

confidence: 51%

Superenhancer reprogramming drives a B-cell–epithelial transition and high-risk leukemia

Zhang

Kashiwagi

et al. 2016

Genes Dev.

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IKAROS is required for the differentiation of highly proliferative pre-B-cell precursors, and loss of IKAROS function indicates poor prognosis in precursor B-cell acute lymphoblastic leukemia (B-ALL). Here we show that IKAROS regulates this developmental stage by positive and negative regulation of superenhancers with distinct lineage affiliations. IKAROS defines superenhancers at pre-B-cell differentiation genes together with B-cell master regulators such as PAX5, EBF1, and IRF4 but is required for a highly permissive chromatin environment, a function that cannot be compensated for by the other transcription factors. IKAROS is also highly enriched at inactive enhancers of genes normally expressed in stem-epithelial cells. Upon IKAROS loss, expression of pre-B-cell differentiation genes is attenuated, while a group of extralineage transcription factors that are directly repressed by IKAROS and depend on EBF1 relocalization at their enhancers for expression is induced. LHX2, LMO2, and TEAD-YAP1, normally kept separate from native B-cell transcription regulators by IKAROS, now cooperate directly with them in a de novo superenhancer network with its own feed-forward transcriptional reinforcement. Induction of de novo superenhancers antagonizes Polycomb repression and superimposes aberrant stem-epithelial cell properties in a B-cell precursor. This dual mechanism of IKAROS regulation promotes differentiation while safeguarding against a hybrid stem-epithelial-B-cell phenotype that underlies high-risk B-ALL.

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Section: Discussionmentioning

confidence: 51%

Superenhancer reprogramming drives a B-cell–epithelial transition and high-risk leukemia

Zhang

Kashiwagi

et al. 2016

Genes Dev.

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“…These include the IKAROS family zinc finger (IKFZ1) [38], Lymphocyte cytosolic protein 1 (LCP) [39], Caspase recruitment domain family, member 11 (CARD11) [40], and IL2-inducible T-cell kinase (ITK)[41]. IKAROS is a zinc finger transcription factor critical for T-cell development [38]. LCP plays a role in the activation of T-cells [39].…”

Section: Resultsmentioning

confidence: 99%

T‐Cell Immunopeptidomes Reveal Cell Subtype Surface Markers Derived From Intracellular Proteins

et al. 2018

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Immunopeptidomes promise novel surface markers as ideal immunotherapy targets, but their characterization by mass spectrometry (MS) remains challenging. Until recently, cell numbers exceeding 109 were needed to survey thousands of HLA ligands. Such limited analytical sensitivity has historically constrained the types of clinical specimens that can be evaluated to cell cultures or bulk tissues. Measuring immunopeptidomes from purified cell subpopulations would be preferable for many applications, particularly those evaluating rare, primary hematopoietic cell lineages. Here, we test the feasibility of immunopeptidome profiling from limited numbers of primary purified human regulatory T cells (TReg), conventional T cells (Tconv) and activated T cells. The combined T-cell immunopeptide dataset reported here contains 13,804 unique HLA ligands derived from 5,049 proteins. Of these, more than 700 HLA ligands were derived from 82 proteins that we exclusively identified from TReg-enriched cells. This study 1) demonstrates that primary, lineage-enriched T cell supbopulations recovered from single donors are compatible with immunopeptidome analysis; 2) presents new TReg-biased ligand candidates; and 3) supports immunopeptidome surveys value for revealing T cell biology that may not be apparent from expression data alone. Taken together, these findings open up new avenues for targeting TReg and abrogating their suppressive functions to treat cancer.

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“…IKZF1 is a zinc finger transcription factor that mediates transcriptional activation and repression, in part through interactions and recruitment of histone-modifying complexes, such as the nucleosome remodeling and deacetylase complex (17, 18), transcriptional elongation complex positive-transcription elongation factor b (19), and polycomb repressor complex 2 (20). The dominant-negative deletions and mutations of IKZF1 remove or perturb function of the N-terminal zinc fingers, resulting in loss of DNA-binding activity but retention of dimerization, resulting in cellular mislocalization (4, 21).…”

Section: Discussionmentioning

confidence: 99%

Synergism of FAK and tyrosine kinase inhibition in Ph+ B-ALL

Churchman¹,

Evans²,

Richmond³

et al. 2016

JCI Insight

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BCR-ABL1+ B progenitor acute lymphoblastic leukemia (Ph+ B-ALL) is an aggressive disease that frequently responds poorly to currently available therapies. Alterations in IKZF1, which encodes the lymphoid transcription factor Ikaros, are present in over 80% of Ph+ ALL and are associated with a stem cell–like phenotype, aberrant adhesion molecule expression and signaling, leukemic cell adhesion to the bone marrow stem cell niche, and poor outcome. Here, we show that FAK1 is upregulated in Ph+ B-ALL with further overexpression in IKZF1-altered cells and that the FAK inhibitor VS-4718 potently inhibits aberrant FAK signaling and leukemic cell adhesion, potentiating responsiveness to tyrosine kinase inhibitors, inducing cure in vivo. Thus, targeting FAK with VS-4718 is an attractive approach to overcome the deleterious effects of FAK overexpression in Ph+ B-ALL, particularly in abrogating the adhesive phenotype induced by Ikaros alterations, and warrants evaluation in clinical trials for Ph+ B-ALL, regardless of IKZF1 status.

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Ikaros mediates gene silencing in T cells through Polycomb repressive complex 2

Cited by 61 publications

References 58 publications

Superenhancer reprogramming drives a B-cell–epithelial transition and high-risk leukemia

Superenhancer reprogramming drives a B-cell–epithelial transition and high-risk leukemia

T‐Cell Immunopeptidomes Reveal Cell Subtype Surface Markers Derived From Intracellular Proteins

Synergism of FAK and tyrosine kinase inhibition in Ph+ B-ALL

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