TAF1: A New Therapeutic Target for Leukemia

Researchers have long been working to identify the molecular basis for myelodysplastic syndromes and acute myeloid leukemia (AML) and understand the differences between malignant and normal hematopoiesis. A study led by Stephen Nimer, MD, may bring the field one step closer.

TAF1 (TBP-associated factor 1) is a large protein and critical subunit of the TFIID complex. In AML, TAF1 has been identified as significant, as it binds to the AML1-ETO (AE) oncogene, a key driver of AML. By understanding TAF1’s role in activating the function of this oncogene, researchers aim to develop therapies to target it directly.

As Nimer, director of the Sylvester Comprehensive Cancer Center at the University of Miami, explains, “Acute promyelocytic leukemia is one of the most curable cancers, so over 90% of [patients] with acute promyelocytic leukemia can be cured with retinoic acid and arsenic—not requiring any chemotherapy, really. That’s been effective, based on targeting the PML/RAR alpha fusion protein. We’ve been trying to develop a similar approach [in AE positive AML].”

Therapeutic Implications of TAF1 and the AML1-ETO Oncogene

TAF1 interacts with the AE oncogene in a crucial way. An enzyme called P300 activates the AE oncogene by acetylating the AE protein. Once acetylated, AE is recognized by bromodomain-containing proteins, and TAF1 possesses a double bromodomain, allowing it to bind to the acetylated AE oncoprotein. This binding is critical for the AE oncogene's function in promoting leukemia.

The therapeutic implications are significant. Since it's challenging to directly target transcription factors like AE, researchers are exploring ways to disrupt the complex formed between AE and TAF1 or to inhibit the enzymes that activate AE.

“Because it's hard to target a transcription factor itself, we've thought if we could break up the complex, or if we could target the enzymes that activate the oncogene, that would be a therapeutic [target],” says Nimer.

Inhibitors of P300 and bromodomain inhibitors are already in clinical trials for other conditions, and some of these bromodomain inhibitors can also target TAF1, Nimer explains. Preclinical studies in mice with leukemia have shown that these inhibitors can prolong their lives. By understanding this interaction, new targeted therapies could be developed to specifically interfere with the TAF1-AE complex, potentially leading to more effective and less toxic treatments for AML.

TAF1's Role in Adult vs Fetal Hematopoiesis

The most surprising and encouraging finding is the distinct role of TAF1 in fetal vs adult hematopoiesis. While TAF1 is essential for fetal hematopoiesis, leading to embryonic lethality and severe anemia upon its deletion during embryogenesis in fetuses, it appears to be largely dispensable for maintaining hematopoiesis in adult mice. In adult mice, knocking out the TAF1 gene results in defective but still robust hematopoiesis, with only mild and transient decreases in blood cell counts.

“TAF1 is a very large protein and thought to be critical for the function of the basic transcriptional machinery, and so it's surprising that the cells can live without this big protein,” says Nimer.

This differential requirement suggests a potential therapeutic window: if TAF1 can be inhibited in adults to treat leukemia, it might do so without causing severe bone marrow suppression or hematopoietic toxicity, which are common and debilitating side effects of conventional chemotherapy. This finding is crucial because it indicates a potential for a "therapeutic window" where TAF1 inhibition could preferentially affect leukemic cells (which are dependent on TAF1) while sparing normal adult hematopoietic stem cells.

“We hope that there's a therapeutic window when you target TAF1, because we've shown it's important in leukemia. It's important in the development of hematopoiesis in the fetus, but in the adult, it doesn't seem to be required,” says Nimer.

In adult mice, the loss of TAF1 primarily affects the differentiation capacity of hematopoietic stem and progenitor cells (HSPCs). While TAF1-null HSPCs show an expansion in their numbers and enhanced self-renewal ability, they exhibit an impaired capacity to differentiate into mature blood cells across multiple lineages (erythroid, B-cell, and T-cell). Specifically, there is a significant increase in the frequency and absolute number of HSPCs in the bone marrow. This is mainly due to impaired differentiation and, to some extent, improved survival of these cells, rather than increased proliferation. TAF1-null HSPCs fail to effectively produce mature blood cells in competitive transplantation experiments and exhibit impaired differentiation towards granulocytes, macrophages, and erythroid cells in vitro. This "slows down" differentiation rather than completely blocking it.

Single-cell RNA sequencing reveals that TAF1 loss specifically impairs the timely activation of differentiation-associated genes (like Klf4, Gfi1, Csf1r, and Cebpb) while leaving major self-renewal genes (like Myb, Myc, and Hoxa9) largely unaffected. TAF1 deficiency leads to decreased promoter accessibility, impaired RNA polymerase II (RNAPII) recruitment and activity at promoters, and a disruption of RNAPII's promoter-proximal pause. This means TAF1 is critical for efficient transcription initiation and elongation of differentiation-related genes.

Clinical Implications of TAF1 Research

While the current research has focused heavily on AML due to the difficulty in developing new therapies for this disease, TAF1's fundamental role in gene transcription suggests broader implications for other cancers. TAF1 has been found to be mutated in some stomach cancers, although its exact role there is not yet understood. It may also play a role in other cancer types.

The insights gained from understanding TAF1's function in transcriptional regulation, TFIID assembly, and chromatin interaction could potentially be translated to therapeutic strategies for these other malignancies if TAF1 is found to be a critical dependency for their growth or survival. Further research is needed to delineate these roles outside of hematological cancers.

Several key questions and challenges remain before TAF1 research can be fully translated into clinical treatments. The primary challenge is that success in mouse models does not guarantee efficacy in human patients. Clinical trials are necessary to confirm the therapeutic potential in humans. Secondly, the current TAF1-impacting compounds are "tool compounds" or first-generation agents. Developing more effective, specific, and safe therapeutic compounds is an ongoing process. Additionally, understanding how TAF1 inhibitors can be effectively combined with other therapies is crucial, as combination approaches often yield better outcomes in cancer treatment.

“We are trying to understand the biochemistry of how the cells continue to live [without TAF1], because that may yield another therapeutic approach when we understand what the dependencies of a cell without TAF1 are,” Nimer explains. “We may be able to ultimately combine a TAF1 inhibitor with something else that we will discover as a result of our studies.”

REFERENCE:

Liu F, Yue J, Tamiro F, et al. TAF1 is required for fetal but not adult hematopoiesis in mice. Dev Cell. 2025 Jul 14:S1534-5807(25)00405-8. doi: 10.1016/j.devcel.2025.06.027. Online ahead of print.