Cracking cancer’s code: New research identifies novel drug target for acute myeloid leukemia treatment

Despite advances in cancer treatment in recent years, five-year survival rates for acute myeloid leukemia (AML) remain low at just 30% on average, according to the National Cancer Institute. Factors in the development of AML are diverse with many different drivers. A longtime goal for scientists in this field is finding a single drug that can treat all types of AML. A team led by The University of Texas Health Science Center at San Antonio (UT Health San Antonio) scientists are closer than ever to this goal with their discovery of how a certain protein in the cell nucleus, paraspeckle component 1 (PSPC1), contributes to AML progression.

“The traditional AML treatment is the ‘3+7’ chemotherapy regimen. But AML is highly diverse, with more than 70 known driver mutations. Even targeted therapies like IDH inhibitors can only treat a small subset of AML patients. Given this diversity, we need a uniform, one-for-all drug target to effectively treat AML,” said one of the study’s primary investigators, Mingjiang Xu, PhD, professor in the Department of Molecular Medicine at the Joe R. and Teresa Lozano Long School of Medicine and CTRC Council Distinguished Chair in Oncology at UT Health San Antonio’s Mays Cancer Center.

Xu’s team published their findings online February 14, 2025, in Cell Stem Cell. Co-primary investigators include Feng-Chun Yang, MD, PhD, tenured professor in the Department of Cell Systems and Anatomy, A.B. Alexander Distinguished Chair in Cancer Research, Mays Cancer Center and Jianlong Wang, PhD, Columbia University Irving Medical Center.

How PSPC1 fuels blood cancer

AML is an aggressive blood cancer that originates in the bone marrow and is known to impair the differentiation of myeloid cells, which leads to overproduction of immature cells. The condition inhibits normal blood cell formation and compromises the immune system. Successful treatment of AML is complicated for many reasons, said Xu. About a third of patients do not respond to chemotherapy and about half of the patients who achieved remission will relapse. Additionally, AML exhibits multiple mutations, often two or more in each cancer cell. Precision treatments may target one mutation but not be effective in other mutations.

PSPC1 is one of three proteins in a paraspeckle — tiny structures inside the cell nucleus believed to regulate gene activity by trapping and releasing RNA molecules. Research in solid tumors shows upregulation of PSPC1 is a strong factor for metastasis in many types of cancer. Upregulation of this protein is higher in AML than any other cancer.

Xu and his research team investigated the role of PSPC1 in AML using both human AML cells and mouse models. They discovered that PSPC1 is not required for normal blood cell formation but is essential for AML development.

In mouse models where PSPC1 was depleted, AML progression was significantly delayed and survival rates improved. Without PSPC1, myeloid cell differentiation resumed, effectively halting cancer progression. This suggests that PSPC1 plays a crucial role in maintaining AML characteristics. When tested in mouse models of different types of AML, knockdown of PSPC1 restored cell differentiation and stopped leukemic progression in each one.

“PSPC1 goes to specific chromatin regions and regulates important pro-leukemic genes through a non-canonical mechanism. When PSPC1 is knocked down, it can no longer promote these leukemic genes, leading to differentiation and apoptosis [cell death] of AML cells. We also found that PSPC1 alone regulates the leukemic gene transcription program consisting of many key leukemic genes,” said Xu.

Concurrent role of PU.1

The mechanism behind PSPC1’s oncogenic role was revealed through its interaction with PU.1, a transcription factor essential for blood and immune cell development. This interaction activated tumor-promoting genes, including NDC1, a gene not previously implicated in AML.

“PSPC1 and the transcription factor PU.1 work together to cooperatively drive the leukemic transcription program. This underlying mechanism makes PSPC1 a novel therapeutic target,” said Xu.

What happens to AML without PSPC1?

Further experiments showed that knocking down PSPC1 led to reduced expression of AML-associated genes, increased myeloid differentiation and a decrease in cancer cell growth. Importantly, PSPC1 knockdown had no adverse effects on normal blood cell formation.

“Targeting PSPC1 could offer a new avenue for AML treatment,” said Xu. “By disrupting its binding to the chromatin and/or interaction with PU.1, we may be able to restore normal myeloid differentiation and inhibit cancer growth.”

Beyond AML

Along with AML, PSPC1 has been identified in 21 different cancer cell lines, primarily in solid tumors where its overexpression contributes to disease progression. This raises the possibility that PSPC1-targeted therapies could have broader applications in oncology. Researchers are now exploring techniques to selectively inhibit PSPC1 in cancer cells while preserving its function in normal cells.

“We used PSPC1 knockout mice to show that PSPC1 inhibition is not toxic — the animals were completely normal even after knocking out PSPC1 and observing them for over two years. This makes PSPC1 an even more attractive drug target, as we can hit it [AML] hard without worrying about severe adverse effects,” said Xu.

Xu said they are currently working with Daohong Zhou, MD, tenured professor of biochemistry and structural biology, associate director for drug development at Mays Cancer Center and director of The University of Texas at San Antonio’s Center for Innovative Drug Discovery to begin testing potential drug candidates that may inhibit PSPC1.

“The development of PSPC1 inhibitors or degraders will have a huge impact not just on AML, but also on solid tumors like lung and prostate cancer, by preventing metastasis. This further increases the significance of our future drug development efforts targeting PSPC1,” said Xu.