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Nynrin Sustains Leukemia Stem Cell Viability via TXNIP Destabilization to Maintain Redox Homeostasis and Confer Venetoclax Resistance [KG-1a RNA-Seq]

ABSTRACT: Acute myeloid leukemia (AML) is driven by chemotherapy-resistant leukemia stem cells (LSCs), which rely on precise regulation of reactive oxygen species (ROS) for survival. We identify NYNRIN as a novel post-transcriptional regulator of LSC redox homeostasis. NYNRIN is selectively overexpressed in ROS-low LSCs and correlates with poor clinical outcomes in AML patients. Genetic targeting of Nynrin in murine models impairs LSC self-renewal, reduces leukemic burden, and prolongs survival, while sparing normal hematopoietic stem and progenitor cells. Mechanistically, NYNRIN binds to TXNIP mRNA, promoting its degradation and maintaining redox balance. Loss of NYNRIN leads to TXNIP stabilization, oxidative stress, mitochondrial dysfunction, and LSC apoptosis, which can be rescued by TXNIP knockdown or ROS scavenging. Notably, Nynrin ablation synergizes with venetoclax to overcome resistance, enhancing LSC cytotoxicity in vitro and in vivo. These findings highlight the NYNRIN-TXNIP-ROS axis as crucial for LSC maintenance and suggest NYNRIN inhibition as a potential therapeutic strategy for relapsed AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313448 | GEO | 2026/06/06

REPOSITORIES: GEO

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Nynrin Sustains Leukemia Stem Cell Viability via TXNIP Destabilization to Maintain Redox Homeostasis and Confer Venetoclax Resistance

Project description:Acute myeloid leukemia (AML) is driven by chemotherapy-resistant leukemia stem cells (LSCs), which rely on precise regulation of reactive oxygen species (ROS) for survival. We identify NYNRIN as a novel post-transcriptional regulator of LSC redox homeostasis. NYNRIN is selectively overexpressed in ROS-low LSCs and correlates with poor clinical outcomes in AML patients. Genetic targeting of Nynrin in murine models impairs LSC self-renewal, reduces leukemic burden, and prolongs survival, while sparing normal hematopoietic stem and progenitor cells. Mechanistically, NYNRIN binds to TXNIP mRNA, promoting its degradation and maintaining redox balance. Loss of NYNRIN leads to TXNIP stabilization, oxidative stress, mitochondrial dysfunction, and LSC apoptosis, which can be rescued by TXNIP knockdown or ROS scavenging. Notably, Nynrin ablation synergizes with venetoclax to overcome resistance, enhancing LSC cytotoxicity in vitro and in vivo. These findings highlight the NYNRIN-TXNIP-ROS axis as crucial for LSC maintenance and suggest NYNRIN inhibition as a potential therapeutic strategy for relapsed AML.

2026-06-06 | GSE311388 | GEO

Nynrin Sustains Leukemia Stem Cell Viability via TXNIP Destabilization to Maintain Redox Homeostasis and Confer Venetoclax Resistance

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Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening (RNA-Seq for Nynrin cko HSC)

Project description:Mitochondria have recently been identified as a critical regulator for the homeostasis of hematopoietic stem cells (HSCs). However, the mechanism underlying HSC regulation still needs to be clarified. Here, we identify transcription factor Nynrin as a novel regulator of HSC maintenance through modulation of mitochondrial function. We demonstrate that Nynrin is highly expressed in HSC under steady and stress state. Nynrin knockout leads to significantly decreased long-term HSC frequency, markedly reduced HSC dormancy, and self-renewal capacity in steady-state and stress hematopoiesis. We observed abnormal mitochondrial metabolism and mitochondrial permeability transition pore (mPTP) opening in Nynrin-deficient HSCs. Notably, Nynrin-deficient HSCs are more compromised in tolerance of irradiation- and 5-fluorouracil-induced stresses and exhibit typical phenotypes of necrosis. In contrast, overexpression of Nynrin in HSC is resistant to the radiation. Mechanistically, Nynrin deletion induces transactivation of Ppif. Overexpression of cyclophilin D (CypD), the protein encoded by the Ppif gene, causes mPTP opening, mitochondrial swelling, ROS overinduction, and cell necrosis. Both blocking the function of CypD by using cyclosporin A (CsA) or reducing the expression of Ppif could inhibit Nynrin deficiency-induced mitochondrial metabolism enhancement and ROS overproduction, thereby evidently rescuing the impairment of HSCs in Nynrin mutant mice. Collectively, our data, for the first time, characterize Nynrin as a critical regulator of HSC function acting through the Ppif/mPTP mitochondria axis and highlight the importance of Nynrin in HSC maintenance. These data provide new insights into the mechanisms for controlling HSC fate.

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Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening （human_HSC_RNA_Seq)

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Nynrin Sustains Leukemia Stem Cell Viability via TXNIP Destabilization to Maintain Redox Homeostasis and Confer Venetoclax Resistance [KG-1a RNA-Seq]

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