Abstract
Hematopoiesis is tightly regulated through various molecular mechanisms, including the ubiquitin proteasome system (UPS). Dysregulation can lead to malignancies, including acute myeloid leukemia (AML). AML is characterized by an abnormal proliferation of immature myeloid cells. F-box ubiquitin E3 ligase, FBXO21, is differentially expressed in both normal and malignant hematopoiesis. FBXO21 has low expression in AML, but high expression correlates to decreased survival in AML patients. At the protein level, AML patients with high blast counts have increased expression of FBXO21, suggesting FBXO21 may play a role in leukemic stem cells (LSCs) to promote progression and survival of AML. This paradoxical relationship between FBXO21 expression and patient survival highlights a major gap in knowledge and the necessity of further studies to understand the role of FBXO21 in AML. We have found that silencing of FBXO21 in AML cell lines and primary AML patient samples leads to increased apoptosis, differentiation, and decreased proliferation. Furthermore, silencing of FBXO21 leads to up-regulation of inflammatory cytokines/chemokines and modulation of MAP kinase pathways, which are known to be involved in the activation of many cytokine signaling pathways. We have identified up-regulation of CXCL10 at both the RNA and protein level, which is known to initiate T-cell recruitment and promote anti-tumor activity within the AML microenvironment. These findings lead us to hypothesize that FBXO21 regulates the maintenance and progression of AML through MAP kinase mediated cytokine signaling pathways. Regulation of cytokines and chemokines play a key role in the progression and maintenance of AML, suggesting FBXO21 may impact disease progression and survival.