Credit: Rhoda Baer
The protein WTAP could play an important role in the development of acute myeloid leukemia (AML), according to new research.
Investigators discovered that AML cells have higher-than-normal levels of WTAP.
But silencing WTAP expression in leukemic cells can suppress proliferation and induce differentiation.
And, in mouse models of AML, knocking down WTAP can reduce tumor growth.
The researchers recounted these findings in a letter to Leukemia.
The team first uncovered high levels of WTAP in AML cells compared to normal peripheral blood mononuclear cells. And they found evidence to suggest that this contributes to abnormal cell behavior.
WTAP levels were not associated with individual cytogenetic abnormalities, but FLT3-ITD and NPM1 mutations were significantly correlated with WTAP expression. And WTAP levels were positively correlated with levels of proliferation-related proteins, anti-apoptotic proteins, oncoproteins, and proteins important for stem cell function.
To gain more insight into the importance of WTAP, the investigators silenced its expression in K562 cells, HL-60 cells, OCI-AML3 cells, and primary AML cells.
“Knocking down this protein, WTAP, greatly suppressed proliferation and induced differentiation,” said study author Hima Bansal, PhD, of The University of Texas Health Science Center at San Antonio.
WTAP knockdown alone did not induce apoptosis, but it did enhance the apoptosis that occurred after the administration of etoposide.
The researchers also examined the role of WTAP in AML using mouse models. They found that tumors derived from WTAP-knockdown cells were significantly smaller and grew significantly slower than tumors derived from cells that expressed WTAP.
Finally, the investigators set out to determine why WTAP is overexpressed in AML. They noted that the Wilms’ tumor 1 (WT1) gene has an oncogenic role in leukemogenesis, and WTAP partners with WT1 to function as a switch gene, regulating the balance between cell quiescence and proliferation.
So the researchers decided to investigate Hsp90, a molecular chaperone that helps stabilize many oncoproteins, including WT1. And they found a direct interaction between Hsp90 and WTAP.
The Hsp90 inhibitor ganetespib promoted the degradation of WTAP in K562, MV4-11, and Kasumi-1 cell lines, as well as in leukemic blasts. In mice, ganetespib inhibited tumor growth.
And experiments suggested that ganetespib-mediated WTAP degradation is dependent on the ubiquitin-proteasome pathway. But the investigators said further research is needed to clarify WTAP’s mechanism of action.
Nevertheless, they believe the results of this research indicate that WTAP could be a promising therapeutic target for AML.
