Notch signaling in the malignant bone marrow microenvironment: implications for a niche-based model of oncogenesis

Fueled by the growing interest in stem cell biology and the promise of regenerative medicine, study of the hematopoietic stem cell (HSC) microenvironment has provided critical insights into normal and malignant hematopoiesis. Notch receptor signaling in this microenvironment is a critical regulator of HSC fate and differentiation. Notch signaling also has the potential to modulate the growth of various malignant cell types, as evidenced by the growing list of hematologic cancers and other malignancies associated with either mutations in Notch genes or alterations in Notch signaling. In both health and disease, activation of Notch signaling predominantly exerts influence through stromal cell interactions with the tumor or stem cell microenvironments. Definitive evidence from transgenic mouse models has shown that alterations in stromal cell signaling from the bone marrow niche can induce malignant outgrowth of preleukemic clones and leukemia. Understanding how Notch receptor signals in the bone marrow microenvironment govern stem cell behavior will advance our understanding of cancer pathogenesis in hematologic malignancies and may have implications for treating metastatic solid tumors involving bone. These microenvironmental interactions are potential therapeutic targets for treating and preventing a variety of diseases, including bone marrow failure disorders, myelodysplastic syndromes, leukemia, and lymphoma.