FAM167A is a key molecule to induce BCR-ABL-independent TKI resistance in CML via noncanonical NF-κB signaling activation

Abstract

Background BCR-ABL-independent drug resistance is a barrier to curative treatment of chronic myeloid leukemia (CML). However, the molecular pathways underlying BCR-ABL-independent tyrosine kinase inhibitor (TKI) resistance remain unclear. Methods In silico bioinformatic analysis was performed to identify the most active transcription factor and its inducer that contribute to BCR-ABL-independent TKI resistance. Tandem mass spectrometry analysis was performed to identify the receptor for the noncanonical NF-κB activator FAM167A. In vitro and in vivo mouse experiments revealed detailed molecular insights into the functional role of the FAM167A-desmoglein-1 (DSG1) axis in BCL-ABL-independent TKI resistance. CML cells derived from CML patients were analyzed using quantitative reverse transcription PCR and flow cytometry. Results We found that NF-κB had the greatest effect on differential gene expression of BCR-ABL-independent TKI-resistant CML cells. Moreover, we found that the previously uncharacterized protein FAM167A activates the noncanonical NF-κB pathway and induces BCR-ABL-independent TKI resistance. Molecular analyses revealed that FAM167A activates the noncanonical NF-κB pathway by binding to the cell adhesion protein DSG1 to upregulate NF-κB-inducing kinase (NIK) by blocking its ubiquitination. Neutralization of FAM167A in a mouse tumor model reduced noncanonical NF-κB activity and restored sensitivity of cells to TKIs. Furthermore, FAM167A and surface DSG1 levels were highly upregulated in CD34+ CML cells from patients with BCR-ABL-independent TKI-resistant disease. Conclusions These results reveal that FAM167A acts as an essential factor for BCR-ABL-independent TKI resistance in CML by activating the noncanonical NF-κB pathway. In addition, FAM167A may serve as an important target and biomarker for BCR-ABL-independent TKI resistance.

Haplotype-specific chromatin looping reveals genetic interactions of regulatory regions modulating gene expression in 8p23.1

“…Function of the FAM167A gene located 27 kb upstream of BLK has recently been shown to be an activator of the non-canonical activation pathway of NFκB, which is potentially important for mechanisms of the inflammatory phenotypes with genetic associations at this locus ( Mentlein et al, 2018 ; Yang et al, 2022 ). We, therefore, retain FAM167A as an SLE candidate gene, acknowledging the existing circumstantial evidence supporting BLK as a participant in the mechanism altering disease risk.…”

“…DIORA-1 is a disordered protein ( Mentlein et al, 2018 ) that is secreted and binds desmoglein-1 (DSG1) to gain cell entry, which then activates NFκB via its non-canonical pathway by liberating NFκB-inhibitor kinase from DSG1. DIORA-1 appears responsible for much BCR-ABL-tyrosine kinase inhibitor resistance in chronic myelogenous leukemia (CML) ( Yang et al, 2022 ). Certainly, DIORA-1 has functional properties that make the level of activity of this gene product attractive for mediating SLE risk.…”

Exosomal miR-29a-3p in the immune microenvironment of spleen deficiency promotes hepatocellular carcinoma lung metastasis by activating FAM167A-α1-integrin-NF-κB signaling axis

“…Finally, miRDB and TargetScan predicted FAM167A as the target gene of miR-29a-3p. FAM167A is found in some leukemias and lymphomas and is typically associated with a poor prognosis [44].…”

“…We also found that exosomal miR-29a-3p in the SD internal environment promotes the metastasis of HCC via activation of the FAM167A-α1integrin-NF-κB signaling pathway. It has been reported [44], that the FAM167A gene can activate the NF-κB pathway and induce BCR-ABL-independent tyrosine kinase inhibitor resistance. The FAM167A protein activates the non-canonical NF-κB pathway by binding to desmoglein-1 (DSG1), a cell adhesion protein.…”

Defining Higher-Risk Chronic Myeloid Leukemia: Risk Scores, Genomic Landscape, and Prognostication

“…Recent additions to the differentially expressed genes which may serve as potential biomarkers of progression or TKI resistance include downregulation of the large HECT E3 ubiquitin ligase HERC1 in leukemic cells [57], FAM167A induced activation of the noncanonical NF-κB pathway in TKI-resistant CML cells [58], and upregulation of exosomal proteins RPL13 and RPL14 in the plasma of imatinib resistant patients [59]. Additionally, the MS4A3 transmembrane protein is downregulated in CML progenitor cells preventing differentiation [60].…”