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Gene expression profiling of MC38 Zfx KO clones in vivo

ABSTRACT: A large fraction of patients with cancer exhibit an intrinsic or adaptive resistance to immunotherapies that aim at boosting T cell responses against tumor cells. To better understand resistance mechanisms in tumor cells, we used CRISPR-Cas9 whole-genome editing to identify mutant tumor cells that are resistant to T cell killing. Among the top hits, we identified the transcription factor zinc-finger protein X-linked (Zfx). Zfx knockout tumor cells are resistant to T cell killing both in vitro and in vivo. Mechanistically we showed that Zfx regulates expression of genes involved in apoptosis pathways and Caspase-3 is one of the central components regulated by Zfx. In addition, ZFX expression is decreased in several human cancer tissues compared to healthy tissues. Female kidney renal clear cell carcinoma (KIRC) patients with high ZFX expression showed significantly better survival compared to patients with low ZFX expression. Our results demonstrate a novel resistant mechanism in tumor cells and suggest that targeting tumor cell intrinsic resistance genes in combination with immune therapies could benefit cancer patients. - The "SAMPLE_ID" sample characteristic is a sample identifier internal to Genentech.

ORGANISM(S): Mus musculus

PROVIDER: GSE276965 | GEO | 2025/12/09

REPOSITORIES: GEO

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Project description:Acute myeloid leukemia (AML) propagates as a cellular hierarchy which is maintained by a rare subpopulation of self-renewing leukemia-initiating cells (LICs). These LICs phenotypically resemble HSCs and early myeloid progenitors, and they are functionally defined by their ability to reconstitute AML in xenografted mice. Common transcriptional regulators are believed to drive self-renewal of LICs and normal stem cells. Examples include the histone methyltransferase, MLL and its main targets, the transcription factors HOXA9 and MEIS1; the polycomb group protein, BMI-1; and the Wnt/β-catenin signaling pathway4-9. In AML patients, LICs have been shown to share broad gene expression signatures with hematopoietic stem cells (HSCs) and, in some cases, with embryonic stem cells (ESCs). Moreover, increased expression of these stem cell signatures has been linked to tumor aggressiveness. Elucidating the molecular determinants of stem cell properties in LICs has the potential to improve AML therapy and clarify the relationship between cancer and stem cell biology in general. Here we show that the propagation of LICs in AML depends on Zfx, a transcription factor required for the self-renewal of ESCs and HSCs. Using mouse models, we found that Zfx is required for AML propagation and LIC maintenance. We defined a Zfx-driven gene expression program in murine LICs that correlates with existing stem cell-related gene expression signatures in AML patients. Using a novel, stroma-based RNAi screening strategy, we identified functionally important Zfx target genes. Two of these genes – FAM92A1 and DOCK7 - are required for human AML cell propagation; moreover, their expression levels strongly correlate with AML patient survival across the full spectrum of AML subtypes. Together, our results characterize a novel gene expression program that orchestrates critical stem cell properties of LICs, and drives aggressiveness of AML. Independent primary MLL-AF9 AML cell lines were created carrying the tamoxifen inducible Cre-ER transgene and either the Zfx wild-type (wt/y) (lines 10977, 10980) or the Zfx conditional (Zfx fl/y) allele (lines 10949, 10950, 10986). AML cells generated from each line were isolated from moribund mice and cultured with or without 4-hydroxytamoxifen for 72 hours to induce Cre. After Cre induction, c-Kit + cells were purified by FACS and processed for microarray studies.

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Gene expression profiling of MC38 Zfx KO clones in vivo

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