ID1 in hematopoiesis and hematologic disorders: novel potentials of a classic differentiation regulator

The basic helix-loop-helix (bHLH) transcription factor family plays a crucial role in regulating cellular differentiation and development. Inhibitor of DNA binding 1 (ID1), which lacks a DNA-binding motif, functions as a dominant-negative inhibitor of class I and II bHLH factors to antagonize their abilities to bind to DNA and transcriptionally regulate target genes. Given that hematopoiesis is a dynamic and intricate process involving the differentiation of hematopoietic stem and progenitor cells into mature lineage cell types, elucidating the regulatory role of ID1 as a differentiation inhibitor within the hematopoietic system is paramount. Physiologically, ID1 is indispensable for maintaining normal bone marrow function and cell fate determination. However, aberrant ID1 expression, driven by pathogenic mechanisms, such as gene mutations or oncogenic kinases, contributes to the initiation and progression of various blood disorders, particularly leukemia. In this review, we comprehensively summarize the expression patterns of ID1 in hematopoietic and stromal cells within the bone marrow niche, and delve into its modulation of blood lineage commitment and development. While some discrepancies in the literature may arise from differences in experimental models or detection methods, it is evident that precise ID1 regulation is crucial for myeloid-lymphoid fate decisions. Moreover, ID1 overexpression is a causal factor in hematologic malignancies. Encouragingly, significant strides have yielded promising antileukemic effects of ID1 inhibitors, both alone and in combination with targeted therapies against oncogenic signaling pathways. Nevertheless, further efforts are needed to develop innovative and practical strategies that modulate ID1 activity to restore and sustain hematopoietic homeostasis.