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IKZF1 as a Master Regulator of Immune Infiltrate Recruitment in Solid Tumors

ABSTRACT: IKZF1 as a Master Regulator of Immune Infiltrate Recruitment in Solid Tumors

PROVIDER: PRJNA436150 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6788190.fastq.gz	Fastqsanger.gz
	SRR6788200.fastq.gz	Fastqsanger.gz
	SRR6788191.fastq.gz	Fastqsanger.gz
	SRR6788201.fastq.gz	Fastqsanger.gz
	SRR6788192.fastq.gz	Fastqsanger.gz

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IKZF1 as a Master Regulator of Immune Infiltrate Recruitment in Solid Tumors

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Efficacy of retinoids in IKZF1-mutated BCR-ABL1 acute lymphoblastic leukemia

Project description:Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations were associated with acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Rexinoid receptor agonists reversed this phenotype, in part by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing a new therapeutic option in IKZF1-mutated ALL. Significance: The outcome of therapy for high-risk acute lymphoblastic leukemia remains suboptimal despite contemporary chemotherapy and the advent of targeted therapeutic approaches. Recent genomic studies have identified deletions or mutations of IKZF1 as a hallmark of high-risk ALL, but an understanding of how IKZF1 alteration contribute to leukemia development are lacking. Here we show that IKZF1 alterations drive lymphoid lineage, a stem cell-like phenotype, abnormal bone marrow adhesion, and poor responsiveness to tyrosine kinase inhibitor (TKI) therapy. Using a high-content screen, we show that retinoids reverse this phenotype in part by inducing expression of wild type IKZF1, and increase responsiveness to TKIs. These findings provide new insight into the pathogenesis of high-risk ALL and potential new therapeutic approaches. Pre-B mRNA profiles of p185 MIG and IK6 cells, DMSO or drug treated, in 3 or 4 replicates, using Illumina HiSeq 2500.

2015-09-04 | E-GEOD-68391 | biostudies-arrayexpress

Tumor Suppressor IKZF1 Mediates Glucocorticoid Therapy Resistance in B Cell Precursor Acute Lymphoblastic Leukemia

Project description:Analysis of the effect of Prednisolone in mouse splenocytes with and without Ikzf1 at gene expression level. The hypothesis tested in the present study was that loss of Ikzf1 affects the induction and repression of the Glucocorticoid receptor target genes. Results provide important information of the differentially expressed genes regulated by Ikzf1 upon Prednisolone treatment, explaining the resistance towards Glucocorticoid-induced apoptosis in splenocytes harboring Ikzf1 loss. Total RNA was obtained from WT and Ikzf1+/- splenocytes subjected to 16 hours Prednsiolone treatment compared to untreated cells.

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T cells expressing modified Fc receptor infiltrate solid tumors and provide long-term anti-tumor protection

Project description:The clinical success of T cells armed with chimeric antigen receptor (CAR-T) to cure patients with hematological malignancies, has demonstrated the immense therapeutic potential of equipping T cells with synthetic receptors. Nonetheless, the scarcity of tumor-specific antigens and the limited capacity of T cells to infiltrate the tumor microenvironment significantly limit its clinical use in solid tumors. Here, we provide evidence of FcγRI expressing CD8+ T cells presence in both mouse and human tumors as well as inflammation sites. Inspired by this discovery, we engineered a novel FcγRI-based receptor for T cells. This design allows T cells to target tumor cells indirectly through antibody intermediates, separating the processes of antigen recognition and T cell activation. This approach allows T cells to initiate killing exclusively against cells with antigen overexpression, thus minimizing on-target off-tumor cytotoxicity. Interestingly, the modified FcγRI expression in T cells unexpectedly induces constitutive expression of the CD11b integrin. This additional effect enables the engineered T cells to efficiently infiltrate the tumor basement membrane and develop an effector memory phenotype, potentially promoting long-term anti-tumor activity. The presence of these effector memory subsets characterized complete responders and mediated tumor regression upon rechallenge. Overall, T cell-mediated ADCC suggests an alternative, novel strategy for conventional CAR-T cell design, enables T cells to differentiate between target cells expressing the same antigen, and overcomes the physical barriers of the tumor microenvironment.

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Project description:Network-based molecular modeling of physiological behaviors has proven invaluable in the study of complex diseases such as cancer, but these approaches remain largely untested in contexts involving interacting tissues such as autoimmunity. Here, using Alopecia Areata (AA) as a model, we have adapted regulatory network analysis to specifically isolate physiological behaviors in the skin that contribute to the recruitment of immune cells in autoimmune disease. We use context-specific regulatory networks to deconvolve and identify skin-specific regulatory modules with IKZF1 and DLX4 as master regulators (MRs). These MRs are sufficient to induce AA-like molecular states in vitro in three cultured cell lines, resulting in induced NKG2D-dependent cytotoxicity. This work demonstrates the feasibility of a network-based approach for compartmentalizing and targeting molecular behaviors contributing to interactions between tissues in autoimmune disease.

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IKZF1 in BCR-ABL1 driven pre-B cells

Project description:In order to investigate the function of IKZF1 in ALL, we isolated bone marrow cells from C57Bl6 mice and transformed them with BCR-ABL1. In a second transduction the BCR-ABL1 driven pre-B cells were transformed either with IKZF1-GFP or empty vector control (GFP) and subjected to gene expression analysis.

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