Notch signaling: a key to the pathogenesis of multiple myeloma?

NEOPLASIA

Cellular interactions mediated by Notch receptors (Notch 1-4) and their cognate ligands (Delta-1, -3, and -4, and Jagged1 and 2 in mammals) play central roles in the generation of cellular diversity and the maintenance of uncommitted progenitors in a variety of developmental systems.¹  On a molecular level, ligand-dependent activation of Notch results in proteolytic cleavage and translocation of the intracellular domain of Notch (Notch-IC) to the nucleus, where it functions to modulate transcription of genes associated with lineage specification, cellular proliferation, and survival. The unique capacity of Notch to function as both a cell-surface receptor and a transcriptional regulator provides a mechanism by which cell-cell interactions can directly influence gene expression in neighboring cells. The effects of Notch signaling are pleiotropic, reflecting both the intrinsic potential of the cell receiving the Notch signal and its microenvironmental context. Thus, depending on the cell type and other signals received, Notch activation may promote or inhibit differentiation, increase proliferation or trigger cell-cycle arrest, induce apoptosis or protect the cell from apoptosis. This context dependence has undoubtedly contributed to some of the controversies surrounding the effects of Notch signaling in different systems.

In the hematopoietic system, Notch signaling is complicated by the number of Notch receptors and ligands expressed by hematopoietic and stromal cells, and by the interactions of Notch with other signaling pathways that comprise the hematopoietic regulatory network.²  Thus, although numerous studies indicate that Notch signaling can promote the maintenance and proliferation of hematopoietic stem cells and progenitors and influence cell fate decisions involving most, if not all, hematopoietic lineages, details regarding specific effects of Notch signaling during normal hematopoiesis—and the cellular and molecular mechanisms responsible for those effects—remain largely undefined. Similarly, while aberrant Notch signaling has been associated with a number of malignancies, the molecular mechanisms involved are varied, and in most cases incompletely defined. Indeed, depending on the context, Notch may act as a tumor suppressor rather than an oncogene.³  In T-cell leukemias carrying the t(7;9) translocation, constitutive activity of Notch-IC contributes to oncogenesis by blocking thymocyte maturation, leading to the accumulation of immature double-negative cells. However, even in this case another signal is likely required to elicit the full malignant phenotype. In several tissues, dysregulated Notch signaling has been shown to act in conjunction with other oncogenes, such as E1A, E6, E7, Ras, or Myc, to promote oncogenesis. While these other oncogenes override the G1-S cell-cycle checkpoint, Notch may inhibit differentiation, promote proliferation, and protect the cell from apoptosis.

The studies by Jundt and colleagues (page 3511) and Nefedova and colleagues (page 3503) in this issue of Blood provide new insights into the potential role of Notch signaling in the pathogenesis of multiple myeloma. Together, these papers underscore the importance of the bone marrow micro-environment in this disease. In addition, the seemingly contradictory conclusions by Jundt et al, that Notch signaling promotes proliferation of myeloma cells, and of Nefedova et al, that Notch activity causes growth arrest, simply exemplify the intricacies of Notch signaling that permit distinct effects depending on the cellular context. Thus, in the presence of particular inductive signals (and/or the absence of inhibitory signals), Notch may promote proliferation, whereas in the presence of a toxic agent Notch signaling may induce cell-cycle arrest as a means of permitting cell survival. Both activities of Notch are likely important in the pathogenesis of myeloma. Additional studies to delineate the precise molecular bases for these effects could allow the Notch pathway to be used as a specific therapeutic target for myeloma,⁴  a potentially major clinical advancement given the lack of curative treatment for this disease.