TXNIP Protein Deficiency Linked to Poor Prognosis for AML Patients, Study Finds

TXNIP Protein Deficiency Linked to Poor Prognosis for AML Patients, Study Finds

Low expression levels of the protein TXNIP — thioredoxin interacting protein — was associated with worse outcomes in people with acute myeloid leukemia (AML), according to the results of a new study.

Artificially increasing the amount of this protein prevented AML cells from growing in a laboratory setting and also increased their sensitivity to the cancer treatment Navitoclax (ABT263), the researchers said.

These findings suggest that TXNIP may be a therapeutic target for future AML treatments.

The study, “TXNIP induces growth arrest and enhances ABT263‐induced apoptosis in mixed‐lineage leukemia‐rearranged acute myeloid leukemia cells,” was published in the journal FEBS Press.

AML is a type of blood cancer characterized by the uncontrolled growth of abnormal blood cells in the bone marrow, which impairs the production of healthy blood cells.

Treatment options for AML are limited. That prompted researchers at the Kyoto University and Tenri Health Care University, both in Japan, to investigate the mechanism behind the excessive blood cell growth so as to aid the development of new treatment strategies for this cancer.

The team had previously identified the TXNIP protein as playing a role in reducing the activity of an antioxidant protein called thioredoxin. That protein also has known roles in the regulation of metabolism, inflammation, and cell growth and death.

TXNIP occurs at reduced levels in different types of cancer cells, including in those in AML, it had previously been shown. Now, the research team first investigated whether that TXNIP reduction was an important indicator for patient prognosis.

Analyzing clinical data, the researchers found that lower TXNIP levels were associated with a “poor prognosis” in patients with relapsed or refractory (resistant) AML.

The team also found that TXNIP expression was lowest in AML cells that had a rearrangement of the MLL gene (MLL-r AML). Two laboratory cell lines derived from patients with MLL-r AML thus were used to study the relationship between TXNIP and AML.

To start, the investigators artificially increased the expression of the protein in these MLL-r AML cell lines. After that step had been performed, the rate of growth in the cells significantly decreased. That led the team to hypothesize that TXNIP is involved with the onset of AML.

Looking more closely at the role of TXNIP in regulating cell growth, the researchers found that its overexpression caused the nucleus of the MLL-r cells to become more permeable, potentially weakening them and causing them to die.

The MLL-r cells with TXNIP overexpression also were found to be more susceptible to autophagy, a natural process in which damaged or unneeded cells are broken down and recycled.

In short, by lowering the levels of the TXNIP protein, the researchers found that the AML cells became more resistant to cell death and continued to grow in an abnormal manner.

Enhancing the levels of TXNIP caused an increase in the activity of another protein, called Beclin-1, which is involved in promoting autophagy and whose activity is hindered by a protein called B-cell lymphoma 2 (Bcl2).

One current experimental treatment, called Navitoclax, is designed to block Bcl2 activity, allowing Beclin-1 to trigger autophagy in cancer cells.

Increasing the levels of TXNIP caused MLL-r AML cell lines to become more sensitive to Navitoclax and thus lowered their survival.

“Our present study shows that TXNIP causes growth arrest and positively regulates autophagy in MLL-r AML cell lines, enhancing the effect of [Navitoclax],” the researchers wrote.

“These findings have the potential to establish a promising therapy against refractory AML with MLL rearrangements,” they concluded.