CRIP1 supports the growth and migration of AML-M5 subtype cells by activating Wnt/β-catenin pathway

Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous hematopoietic disorder. To effectively eradicate AML, it is urgent to develop new therapeutic approaches and identify novel molecular targets. In silico analysis indicated that the expression of cysteine-rich intestinal protein 1 (CRIP1) was significantly elevated in AML cells and correlated with worse overall survival of the AML patients. However, its specific roles in AML remain elusive. Here we demonstrated that CRIP1 acted as a key oncogene to support AML cell survival and migration. Using a loss-of-function analysis, we found that CRIP1 silencing in U937 and THP1 cells by lentivirus-mediated shRNAs resulted in a decrease in cell growth, migration and colony formation, and an increase in chemosensitivity to Ara-C. CRIP1 silencing induced cell apoptosis and G1/S transition arrest. Mechanically, CRIP1 silencing caused inactivation of Wnt/β-catenin pathway through upregulating axin1 protein. The Wnt/β-catenin agonist SKL2001 markedly rescued the cell growth and migration defect induced by CRIP1 silencing. Our findings reveals that CRIP1 may contribute to AML-M5 pathogenesis and represent a novel target for AML-M5 treatment.

 

Comments:

The provided information suggests that cysteine-rich intestinal protein 1 (CRIP1) plays a crucial role in acute myeloid leukemia (AML), particularly in the AML-M5 subtype. AML is a diverse and complex hematopoietic disorder, and understanding the specific molecular targets and mechanisms involved is essential for developing effective therapeutic strategies.

In this study, in silico analysis indicated that CRIP1 expression was significantly increased in AML cells and was associated with poorer overall survival in AML patients. To investigate the specific roles of CRIP1 in AML, the researchers conducted loss-of-function experiments using lentivirus-mediated short hairpin RNAs (shRNAs) to silence CRIP1 in U937 and THP1 AML cell lines.

The results demonstrated that CRIP1 depletion led to several important effects on AML cells. Firstly, it decreased cell growth, migration, and colony formation, suggesting that CRIP1 is involved in promoting the survival and migration of AML cells. Additionally, CRIP1 silencing increased the sensitivity of AML cells to Ara-C, a commonly used chemotherapeutic agent for AML treatment.

Furthermore, CRIP1 silencing induced apoptosis (programmed cell death) and caused G1/S transition arrest, which refers to a delay in the cell cycle progression from the G1 phase to the S phase. These findings suggest that CRIP1 plays a role in cell cycle regulation and cell survival in AML.

The study also investigated the underlying molecular mechanism through which CRIP1 functions in AML. It was found that CRIP1 silencing led to the inactivation of the Wnt/β-catenin pathway. This pathway is known to be dysregulated in various cancers and can promote cell proliferation and survival. The inactivation of the Wnt/β-catenin pathway in AML cells was mediated by the upregulation of axin1 protein, which acts as a negative regulator of the pathway.

To further confirm the importance of the Wnt/β-catenin pathway in CRIP1-mediated effects, the researchers used a Wnt/β-catenin agonist called SKL2001. They found that treating CRIP1-depleted AML cells with SKL2001 rescued the defects in cell growth and migration, indicating that the activation of the Wnt/β-catenin pathway could counteract the effects of CRIP1 silencing.

In summary, this study demonstrates that CRIP1 acts as an oncogene in AML, particularly in the AML-M5 subtype. It supports AML cell survival and migration, and its silencing leads to decreased cell growth, migration, colony formation, and increased chemosensitivity. The mechanism of action involves the inactivation of the Wnt/β-catenin pathway through the upregulation of axin1 protein. These findings suggest that CRIP1 may represent a novel therapeutic target for the treatment of AML-M5. Further research and validation are necessary to fully understand the potential of targeting CRIP1 in AML therapy.