Xiangao Huang

PAXIP1-PAGR1 directs cohesin recruitment during break-induced telomere repair

Soo Yeon Hwang, Xiaoying Wu, Xiangao Huang, Fei Li et autres

Abstract Cohesin is a conserved multiprotein complex (SMC1, SMC3, RAD21, and either STAG1 or STAG2) that organizes three-dimensional genome architecture and regulates chromosome segregation, gene expression, and DNA damage repair 1–4 . Following double-strand breaks (DSBs), cohesin is recruited to sites of …

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CDK4/6i Reverses MEIS2 Inhibition of CRL4CRBN and Promotes BCMA Loss to Enhance IMiD/CELMoD Therapy in Multiple Myeloma

Xiangao Huang, David Jayabalan, Maurizio Di Liberto, Zhengming Chen et autres

MEIS2 was identified biochemically as a substrate of cereblon (CRBN), a receptor of the CRL4 CRBN E3 ubiquitin ligase required for the anti-myeloma activity of immunomodulatory drugs (IMiD)s and the second generation cereblon E3 ligase modulatory drug (CELMoD). However, the function and …

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BRG1-mediated suppression of ferroptosis underlies BTK inhibitor resistance

Soo‐Yeon Hwang, Xiangao Huang, Helgi Nikolli, Belem Yoval‐Sánchez et autres

Resistance to Bruton's tyrosine kinase inhibitors (BTKi) remains a major therapeutic challenge in B-cell malignancies. Here, we identify chromatin remodeler BRG1-mediated suppression of ferroptosis as a central mechanism of BTKi resistance in mantle cell lymphoma (MCL), in which aberrant BRG1-dependent transcription program …

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Intracellular Activation of Dual-Pharmacophore Artezomib Enhances Selective Cytotoxicity in Hematologic Malignancies

Daqiang Li, Xiangao Huang, Zoe Chow, Jianxiang Ye et autres

We describe DQ-9, a dual-pharmacophore artezomib analogue that combines selective inhibition of immunoproteasome β5i with iron-dependent activation of artemisinin. DQ-9 exploits the elevated labile iron pool characteristic of hematologic malignancies, yielding selective cytotoxicity toward leukemia and multiple myeloma cells. DQ-9 affords sustained …

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Overcoming therapy resistance with multi-targeted CAR-T cells secreting bispecific antibody (BsAb) for the treatment of B-cell malignancies

Qing Yin, Jing Gao, Xiangao Huang, Allen Y. H. Hu et autres

Abstract Adoptive T-cell immunotherapies have revolutionized the treatment landscape for aggressive B-cell malignancies. Despite high rates of initial complete remission, more than half of patients eventually relapse. While T cell-mediated cytotoxicity remains a powerful therapeutic mechanism, recent attention has turned toward targeting …

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CDK4/6 Inhibition Reverses MEIS2 Suppression of CRL4 CRBN to Enhance Immunomodulatory Drug Therapy in Multiple Myeloma

Xiangao Huang, David S. Jayabalan, Maurizio Di Liberto, Zhengming Chen et autres

Abstract MEIS2 was identified biochemically as a substrate of cereblon (CRBN), a receptor of the CRL4 CRBN E3 ubiquitin ligase required for the anti-myeloma activity of immunomodulatory drugs (IMiD)s and CELMoDs. However, its function in myeloma is unknown. We discovered that MEIS2 …

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Leveraging BRG1 Driven Ferroptosis Resistance to Overcome Treatment Resistance

Soo‐Yeon Hwang, Helgi Nikolli, Belem Yoval‐Sánchez, Peter Martin et autres

Resistance to Bruton's tyrosine kinase inhibitors (BTKi) remains a major therapeutic challenge in B-cell malignancies, limiting treatment durability. Here, we identify ferroptosis suppression as a central mechanism of BTKi resistance in mantle cell lymphoma (MCL). Aberrant BRG1 activity protects cells from BTKi-induced …

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CDK4/6 Inhibition Reverses MEIS2 Inhibition of CRL4CRBN By Both Disrupting MEIS2-CRBN Association and Opposing Regulation of MEIS2 and CRBN Synthesis That Enhances IMiD Therapy in Multiple Myeloma

Xiangao Huang, David S. Jayabalan, Maurizio Di Liberto, Zhengming Chen et autres

The immunomodulatory drugs (IMiDs) lenalidomide (Len) and pomalidomide (Pom) are standard of care for multiple myeloma (MM). Cereblon (CRBN), a component of the CRL4CRBN E3 ligase, is required for IMiD's anti-myeloma activity. Binding of IMiD to CRBN promotes the recruitment of transcription …

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Disrupting IL10 Signaling Overcomes Compound Copy Number Variation-Driven Clinical Resistance to CDK4/6 and BTK Inhibition in Mantle Cell Lymphoma

Maurizio Di Liberto, Yang Sheng Hu, Xiangao Huang, Giorgio Inghirami et autres

Drug resistance remains a formidable challenge in MCL, largely due to unrestrained proliferation of MCL cells driven by aberrant Cyclin D1 and CDK4 expression. In preclinical studies, inhibition of CDK4/6 not only induces early G1 cell cycle arrest but also reprograms MCL …

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Harnessing Btki Therapy By CDK4/6i Control of T Effector Memory Cells and T Cell Surveillance in Mantle Cell Lymphoma

Maurizio Di Liberto, Yang Sheng Hu, Xiangao Huang, Giorgio Inghirami et autres

Drug resistance remains a formidable challenge in mantle cell lymphoma (MCL). Cell cycle dysregulation driven by aberrant Cyclin D1 and CDK4 expression is a hallmark for MCL, providing a rationale for targeting the cell cycle in MCL therapy. We have demonstrated in …

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HARNESSING BTKI THERAPY BY CDK4/6I CONTROL OF T CELL SURVEILLANCE

Selina Chen‐Kiang, Massimiliano Di Liberto, Xiangao Huang, Giorgio Inghirami et autres

Introduction: Drug resistance remains a formidable challenge in mantle cell lymphoma (MCL). Cell cycle dysregulation driven by aberrant Cyclin D1 and CDK4 expression is a hallmark for MCL. By inhibition of CDK4/6, we have developed a novel strategy that both inhibits proliferation …

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Supplementary Figure S2 from Cell-Cycle Reprogramming for PI3K Inhibition Overrides a Relapse-Specific C481S BTK Mutation Revealed by Longitudinal Functional Genomics in Mantle Cell Lymphoma

David Chiron, Maurizio Di Liberto, Peter G. Martin, Xiangao Huang et autres

NIK and p52 of the alternative NF-kappaB pathway are expressed in JEKO-1 MCL cells and not modulated by targeting of CDK4 with PD 0332991 in combination with ibrutinib.