Figure 1: Tetraspanins organize protein interaction networks.
Fig. 1. Tetraspanins organize protein interaction networks.

Hematopoietic stem cells (HSCs) are rare, multipotent cells that give rise to all of the cells found in the blood. HSCs are largely quiescent, with approximately 75% of them in the G0 phase of the cell cycle. In response to stressful stimuli (e.g., infection or injury), HSCs are induced to proliferate and differentiate to supply the effector cells necessary to resolve the acute insult. HSCs must fairly quickly return to a quiescent state, however, as sustained proliferation leads to impaired HSC function. Indeed, chronic exposure to stressful stimuli contributes to cytopenias in patients with chronic infections, autoimmune disorders and other bone marrow failure syndromes. Understanding exactly how inflammatory signals affect HSCs is therefore critical to the design of therapeutic interventions to protect the function of stressed HSCs.

Fig. 2. DREAM pathway. Activation of p53 leads to production of p21, which inhibits CDK/cyclins that phosphorylate p107 and p130 and target them for degradation. Hypo-phosphorylated p107 and p130 help form the DREAM transcriptional repressor complex that binds at E2F and CHR sites to repress cell cycle genes.

We recently discovered that the tetraspanin family member CD53 is highly upregulated on HSCs in response to multiple inflammatory and proliferative stressors. Tetraspanins are a family of transmembrane proteins that organize protein interaction networks on the cell surface to regulate a variety of cellular processes such as proliferation, survival, and homing (Figure 1). We have generated a Cd53-/- mouse, and found that while HSC numbers and function are largely normal under homeostatic conditions, loss of CD53 significantly impairs HSC function in the context of inflammatory stress. Mechanistically, CD53 promotes the return of HSC quiescence via activation of the “DREAM” transcriptional repressor complex. DREAM involves the RB-like family members p107/Rbl1 and p130/Rbl2, and inhibits the expression of cell cycle genes in response to p53 and p21 activation (Figure 2). Ongoing studies in the lab are aimed at understanding the connection between CD53 and DREAM activation, as well as the specific roles of CD53 and the DREAM complex in protecting stressed HSCs. Finally, CD53 expression is increased in HSCs deficient for the epigenome regulators Tet2 and Dnmt3a. Mutations in these genes are commonly associated with age-related clonal hematopoiesis, which involves the expansion of mutant HSCs in response to inflammation and predisposes to the development of hematopoietic malignancies as well as all-cause mortality. We are currently exploring the role of CD53 in the clonal expansion of mutant HSCs.

Finally, In addition to regulating HSCs, CD53 is essential for normal B cell development. We have shown that it promotes early B cell development via interaction with IL7-R and promotion of IL7-R signaling, and we are currently exploring its role in both normal and malignant B cell trafficking. Specifically, we have found that loss of CD53 markedly impairs the ability of B cells to home to the bone marrow, and we are identifying the interaction partners and mechanisms by which it normally promotes this process. Given the importance of bone marrow homing to the growth of malignant B cells, we are currently also testing CD53 as potential therapeutic target for B cell malignancies.