MIAMI, FLORIDA (July 24, 2025) – A new study led by Stephen D. Nimer , M.D.,director of Sylvester Comprehensive Cancer Center , part of the University of Miami Miller School of Medicine, shows how a key molecule regulates the generation of new blood cells, a process called hematopoiesis that goes awry in cancer. The findings have the potential to lead to new therapeutic strategies targeting the molecule, a regulator of gene activity called TAF1.
The new findings "not only challenge prevailing models of hematopoietic regulation but also lay the groundwork for innovative clinical applications," said Sylvester researcher Ramin Shiekhattar , Ph.D., co-leader of the Cancer Epigenetics Program at Sylvester and chief of the Division of Cancer Genomics and Epigenetics. He is also an author on the study, which was published July 16 in the journal Developmental Cell.
Pairing Up
Long-time collaborators, Nimer, Shiekhattar and colleagues previously reported that knocking out TAF1 quelled disease in a model of acute myeloid leukemia driven by the aberrant gene regulator AML1-ETO.
TAF1 seems to work together with the AML1-ETO protein to turn on cancer-causing genes, the researchers showed.
TAF1 is part of a large molecular machine that binds to DNA and helps activate genes. The machine helps initiate the process of transcription, which involves generating RNA from the DNA code.
In the current study, the researchers took a closer look at TAF1 to better understand how it operates in normal blood cell development.
Fostering Cell Maturation
Blood cells arise from immature cells in the bone marrow called hematopoietic stem cells (HSCs).
HSCs are powerful cells. They are used for transplantation. And they do two key things: they self-renew and they give rise to mature cell types including immune cells (both T cells and B cells), myeloid cells (neutrophils and monocytes), platelets, and red blood cells, in a process called lineage commitment.
TAF1 is needed to properly turn on genes involved in lineage commitment in adults, but it has a reduced role in HSC self-renewal, according to these just published findings. The data also demonstrate that TAF1 operates differently during embryogenesis, when there is a much higher demand for blood production.
"TAF1 appears to serve as a key molecular switch that integrates transcriptional signals to balance stem cell maintenance with lineage commitment in adults," said Shiekhattar.
The findings challenge the prevailing view of how TAF1 functions, said the researchers. TAF1 and its associated machinery were long thought to be universally necessary for turning on genes throughout the life of every cell.
The new study adds to growing evidence that TAF1 instead has a more fine-tuned role in gene regulation, in this study, preferentially turning on genes that prompt HSCs to differentiate into mature blood cells.
"The most surprising discovery is that adult HSCs can survive without an important general transcription factor, and that the TAF1 loss only affects the activation of differentiation-associated genes, not the self-renewal-promoting genes," said Sylvester researcher Fan Liu , Ph.D., the first author of the study.
Nimer's team, working with Sylvester bioinformatics specialist Felipe Beckedorff , Ph.D., delved even further into how TAF1 turns on genes. They found that TAF1 both prompts the initiation of transcription and releases a separate brake on the transcription process.
Questions for future studies include whether TAF1 performs similar functions in other stem cell compartments relevant for cancer, such as in the colon or brain.
Meanwhile, the new findings provide momentum to studies investigating TAF1-targeting agents, which are under development.
One challenge in hematology is finding drugs that are powerful enough to kill the cancer cells but not kill normal blood cell development. The data suggest that TAF1 inhibitors might fulfill this criterion: knocking out TAF1 did not stop stem cell self-renewal or blood cell production, which are essential for life.
"A key question that we needed to address was; if you successfully target TAF1, do you compromise normal blood production? What this paper says is no," said Nimer.
Other potential therapeutic use-cases include harnessing TAF1 to improve the expansion of HSCs in petri dishes, a process that could improve stem cell transplantation.
