Sajesan Aryal

A Perturb-seq map of a differentiation hub reveals synergistic vulnerabilities in KMT2A-rearranged acute myeloid leukemia

Sajesan Aryal, Brittany M. Curtiss, Xinyue Zhou, Rui Lu et autres

KMT2A-rearranged acute myeloid leukemia is driven by epigenetic dependencies yet remains clinically resistant to therapies targeting individual regulators, indicating that resistance reflects compensatory regulation across an epigenetic network. A systematic understanding of this compensatory network has been lacking. To address this gap, …

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Causal interaction inference of compensatory structures from single-cell perturb-seq in AML

Changde Cheng, Sajesan Aryal, Brittany M. Curtiss, Xinyue Zhou et autres

Abstract Resistance to single-agent therapy in acute myeloid leukemia (AML) often arises from compensatory epigenetic circuits. We present a causal inference framework that treats therapy as an intervention (do-operator) and defines resistance as the deviation of dual perturbations from the additive expectation …

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Paralog interdependency between MEF2C and MEF2D sustains protein stability and leukemia maintenance in KMT2A-rearranged AML

Pengcheng Zhang, Xinyue Zhou, Sajesan Aryal, Jianfeng Cai et autres

Abstract Acute myeloid leukemia (AML) is characterized by lineage infidelity, transcriptional dysregulation, and frequent resistance to standard therapies. Among AML subtypes, those harboring KMT2A (MLL) rearrangements (KMT2A-r) remain particularly aggressive and refractory to current treatments. Transcription factors such as MEF2C play a …

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A perturb-seq map of a differentiation hub reveals synergistic vulnerabilities in KMT2A-rearranged AML

Sajesan Aryal, Brittany M. Curtiss, Xinyue Zhou, Rui Lu et autres

Abstract Introduction: KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) is characterized by epigenetic dependencies, yet it often remains clinically resistant to therapies targeting individual regulators. This suggests that resistance is not attributable to any single regulator but is an emergent property of a …

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Acute depletion of HOXA9 reveals its direct role in cis-elements regulation and 3D genome organization during Acute Myeloid Leukemia

Qili Shi, Sajesan Aryal, Qiushi Jin, Xinyue Zhou et autres

Abstract In normal hematopoiesis, HOXA9 maintains early hematopoietic progenitors and is silenced during differentiation. Failure to silence HOXA9 blocks hematopoietic differentiation and leads to leukemia. In acute myeloid leukemia (AML), it is overexpressed in over 70% of cases with diverse genetic alternations …

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Perturbation of iNKT differentiation during clonal hematopoiesis from rewiring of inflammation and lipid presentation

Francesca Luca, Alana Franceski, Paran Goel, Brittany L. Crown et autres

Abstract Invariant Natural Killer T (iNKT) cells are a rare, non-conventional T cell subset that recognize lipid antigens presented by the MHC class I-like molecule CD1d. Upon activation, iNKTs rapidly produce a wide range of cytokines, enabling them to serve as first …

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Son haploinsufficiency in hematopoietic cells disrupts the crosstalk between splicing fidelity and chromatin accessibility, impairing lymphoid lineage commitment

Saeed ZakaKhosravi, Amr Elkholy, James M. Murphy, Xinyue Zhou et autres

Abstract Introduction Hematopoietic lineage specification and differentiation rely on precise gene regulation, integrating transcription factors with RNA splicing and chromatin remodeling. The SON gene encodes a multi-domain protein essential for transcriptional regulation, RNA splicing, and nuclear speckle organization. We previously showed that …

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Activation of a nongenetic AHR-ELMSAN1 axis optimizes BET-targeting therapy and suppresses leukemia stem cells in preclinical models

Xinyue Zhou, Steven Moreira, Cecilia Restelli, Hong Wang et autres

Developing strategies to enhance the response to bromodomain and extraterminal domain (BET) inhibitors and effectively eradicate cancer stem cells would represent a major cancer treatment advance against leukemia. Through a functional CRISPR screen, we identified the aryl hydrocarbon receptor (AHR), a ligand-activated …

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Abstract Thu032: Systematic CRISPR Knockout Screen Uncovers Epigenetic Barriers to Direct Cardiac Reprogramming

Anteneh Getachew Woldemariam, Sajesan Aryal, Hui Li, William Peng et autres

Background: The direct conversion of human fibroblasts into induced cardiomyocytes (iCMs) holds great promise for generating mature cardiomyocytes for clinical applications. However, the process remains inefficient, and the underlying reprogramming mechanisms are not well understood. Given the crucial role of epigenetic regulation …

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The acute myeloid leukemia microenvironment impairs neutrophil maturation and function through NF-κB signaling

Paran Goel, Sajesan Aryal, Alana Franceski, Valeriya Kuznetsova et autres

ABSTRACT: Acute myeloid leukemia (AML), an aggressive hematological malignancy, is driven by oncogenic mutations in stem and progenitor cells that give rise to AML blasts. Although these mutations are well characterized, their impact on healthy hematopoiesis, those blood cells exposed to AML …

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Abstract 219: Uncovering synergistic and antagonistic interactions in epigenetic therapeutics using perturb-seq

Changde Cheng, Rui Lu, Sajesan Aryal, Doug Welsch

Abstract Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by genetic and epigenetic dysregulation, including aberrant activity of chromatin modifiers. The complex interactions among these modifiers and regulators in AML pathogenesis remain poorly understood, posing significant challenges to developing effective combination …

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Phytochemicals screening, antimicrobial activities and statistical validation of bioactive compounds of Morella rubra Sieb.et Zucc

Janardan Lamichhane, Sajesan Aryal, Abhishek Prajapati, Trishna Lamichhane et autres

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