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FBXO3-mediated DUSP9 ubiquitination promotes leukemia stem cell maintenance and tyrosine kinase inhibitor resistance in chronic myeloid leukemia

ABSTRACT: Eradicating leukemic stem cells (LSCs) and overcoming tyrosine kinase inhibitor (TKI) resistance is urgent for chronic myeloid leukemia (CML) treatment. We find that F-box protein 3 (FBXO3) is highly upregulated in CD34+ CML stem cells from TKI-resistant patients and identify it as an innovative CML-LSC marker via single-cell RNA sequencing (scRNA-seq). FBXO3 deficiency induces apoptosis and reduces proliferation of CML cell lines and LSCs in vitro and in vivo, with minimal effects on normal CD34+ hematopoietic stem cells (HSCs). Mechanistically, FBXO3 interacts with DUSP9 to promote its ubiquitination and activate the MAPK pathway, critical for CML cell activity. DUSP9 knockdown partially reverses FBXO3 deficiency-mediated LSC elimination. Furthermore, FBXO3 inhibitor monotherapy or combination with imatinib effectively eradicates CML-LSCs, overcomes TKI resistance, and spares normal hematopoiesis. Collectively, our findings highlight FBXO3’s role in CML progression and support combining FBXO3 inhibitors with TKIs for durable LSC elimination.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Bone Marrow

DISEASE(S): Chronic Myeloid Leukemia

SUBMITTER: Xudong Li

LAB HEAD: Xudong Li

PROVIDER: PXD073522 | Pride | 2026-01-25

REPOSITORIES: Pride

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Project description:Tyrosine kinase inhibitors (TKI) are highly effective in treatment of chronic myeloid leukemia (CML) but do not eliminate leukemia stem cells (LSC), which remain a potential source of relapse. TKI treatment effectively inhibits BCR-ABL kinase activity in CML LSC, suggesting that additional kinase-independent mechanisms contribute to LSC preservation. We investigated whether signals from the bone marrow (BM) microenvironment protect CML LSC from TKI treatment. Coculture with human BM mesenchymal stromal cells (MSC) significantly inhibited apoptosis and preserved CML stem/progenitor cells following TKI exposure, maintaining colony forming ability and engraftment potential in immunodeficient mice. We found that the N-Cadherin receptor plays an important role in MSC-mediated protection of CML progenitors from TKI. N-Cadherin-mediated adhesion to MSC was associated with increased cytoplasmic N-Cadherin-M-NM-2-catenin complex formation, as well as enhanced M-NM-2-catenin nuclear translocation and transcriptional activity. Increased exogenous Wnt-mediated M-NM-2-catenin signaling played an important role in MSC-mediated protection of CML progenitors from TKI treatment. Our results reveal a close interplay between N-Cadherin and the Wnt-M-NM-2-catenin pathway in protecting CML LSC during TKI treatment. Importantly, these results reveal novel mechanisms of resistance of CML LSC to TKI treatment, and suggest new targets for treatment designed to eradicate residual LSC in CML patients. RNA was obtained from CML CD34+ cells treated with or without IM (5M-NM-<M) and MSC for 96 hours, amplified, labeled and hybridized to GeneChip 1.0 arrays (Affymetrix, Santa Clara, CA). Microarray data analysis was performed using R (version 2.9) with genomic analysis packages from Bioconductor (version 2.4). The 33297 probes represented on the microarray were filtered by cross-sample mean, and for standard deviation of greater than the 25% quantile, yielding 18624 probes representing 12553 genes. Linear regression was used to model the gene expression with the consideration of a 2x2 factorial design and matched samples. Differentially expressed genes were identified by calculating empirical Bayes moderated t-statistic, and p-values were adjusted by FDR using the M-bM-^@M-^\LIMMAM-bM-^@M-^] package. Gene Set Enrichment Analysis (GSEA) was performed using GSEA software version 2.04 to detect enrichment of predetermined gene sets using t-scores from all genes for 1263 gene sets in the C2 (curated gene sets) category from the Molecular Signature Database (MsigDB).

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	40070-K562-IP-1.mzTab	Mztab
	40070-K562-IP-1.raw	Raw
	40070-K562-IP-2.mzTab	Mztab
	40070-K562-IP-2.raw	Raw
	40070-K562-IP-3.mzTab	Mztab

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FBXO3-mediated DUSP9 ubiquitination promotes leukemia stem cell maintenance and tyrosine kinase inhibitor resistance in chronic myeloid leukemia

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