Unveiling the complexity of transcription factor networks in hematopoietic stem cells: implications for cell therapy and hematological malignancies

Abstract

The functionality and longevity of hematopoietic tissue is ensured by a tightly controlled balance between self-renewal, quiescence, and differentiation of hematopoietic stem cells (HSCs) into the many different blood lineages. Cell fate determination in HSCs is influenced by signals from extrinsic factors (e.g., cytokines, irradiation, reactive oxygen species, O2 concentration) that are translated and integrated by intrinsic factors such as Transcription Factors (TFs) to establish specific gene regulatory programs. TFs also play a central role in the establishment and/or maintenance of hematological malignancies, highlighting the need to understand their functions in multiple contexts. TFs bind to specific DNA sequences and interact with each other to form transcriptional complexes that directly or indirectly control the expression of multiple genes. Over the past decades, significant research efforts have unraveled molecular programs that control HSC function. This, in turn, led to the identification of more than 50 TF proteins that influence HSC fate. However, much remains to be learned about how these proteins interact to form molecular networks in combination with cofactors (e.g. epigenetics factors) and how they control differentiation, expansion, and maintenance of cellular identity. Understanding these processes is critical for future applications particularly in the field of cell therapy, as this would allow for manipulation of cell fate and induction of expansion, differentiation, or reprogramming of HSCs using specific cocktails of TFs. Here, we review recent findings that have unraveled the complexity of molecular networks controlled by TFs in HSCs and point towards possible applications to obtain functional HSCs ex vivo for therapeutic purposes including hematological malignancies. Furthermore, we discuss the challenges and prospects for the derivation and expansion of functional adult HSCs in the near future.

Hematopoietic stem cell division is governed by distinct RUNX1 binding partners

“…A defined number of HSC clones are born during early embryonic development, and these cells are responsible for sustaining the entire blood system throughout life. Clonal dynamics and cell fate decisions are controlled by extrinsic factors such as hypoxia, cytokines and ROS, and intrinsic factors including transcription factors, cell cycle regulators and epigenetic modifiers, both in normal hematopoiesis and hematopoietic malignancies 38 . The transcription factor RUNX1 is essential for definitive hematopoiesis and binds to DNA with cofactors including CBFý to activate expression of hematopoietic target genes 32 .…”