Research Papers:
FGR Src family kinase causes signaling and phenotypic shift mimicking retinoic acid-induced differentiation of leukemic cells
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Abstract
Noor Kazim1, Wang Peng2, Jianbo Yue2,3 and Andrew Yen1
1 Department of Biomedical Science, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
2 Department of Biomedical Science, City University of Hong Kong, Hong Kong, PRC
3 Current address: Division of Natural and Applied Sciences, Synear Molecular Biology Lab, Duke Kunshan University, Kunshan, China
Correspondence to:
Andrew Yen, | email: | [email protected] |
Keywords: cancer biology and cell cycle regulation; retinoic acid(RA); FGR Src-family-kinase; cancer differentiation-therapy; leukemia
Received: October 14, 2024 Accepted: March 06, 2025 Published: March 21, 2025
ABSTRACT
Retinoic acid (RA), an embryonic morphogen, is used in cancer differentiation therapy, causing extensive gene expression changes leading to cell differentiation. This study reveals that the expression of the Src-family kinase (SFK), FGR, alone can induce cell differentiation similar to RA. Traditionally, RA’s mechanism involves transcriptional activation via RAR/RXR(Retinoic Acid Receptor/Retinoid X Receptor) nuclear receptors. In the HL-60 human myelo-monocytic leukemia model, an actively proliferating phenotypically immature, lineage bipotent NCI-60 cell line. RA promotes myeloid lineage selection and maturation with G1/0 growth inhibition. This study finds that FGR expression alone is sufficient to induce differentiation, marked by CD38, CD11b, ROS, and p27(kip1) expression, characteristic of mature myeloid cells.
To understand the mechanism, signaling attributes promoting RA-induced differentiation were analyzed. RA induces FGR expression, which activates a novel cytosolic macromolecular signaling complex(signalsome) driving differentiation. RA increases the abundance, associations, and phosphorylation of signalsome components, including RAF, LYN, FGR, SLP-76, and CBL, which appear as nodes in the signalsome. These traditionally cytosolic signaling molecules go into the nucleus. RAF complexes with a retinoic acid-response element (RARE) in the blr1 gene promoter, where the induced BLR1 expression is essential for RA-induced differentiation. We find now that FGR expression mimics RA’s enhancement of signalsome nodes, RAF expression, and phosphorylation, leading to BLR1 expression. Notably, FGR induces the expression of genes targeted by RAR/RXR, such as cd38 and blr1, even without RA. Thus, FGR triggers signaling events and phenotypic shifts characteristic of RA. This finding represents a paradigm shift, given FGR’s historical role as a pro-proliferation oncogene.

PII: 28705