CD48 on hematopoietic progenitors regulates stem cells and suppresses tumor formation

Abstract

The proliferation and differentiation of adult stem cells is balanced to ensure adequate generation of differentiated cells, stem cell homeostasis, and guard against malignant transformation. CD48 is broadly expressed on hematopoietic cells but excluded from quiescent longterm murine HSCs. Through its interactions with CD244 on progenitor cells, it influences HSC function by altering the BM cytokine milieu, particularly IFN␥. In CD48-null mice, the resultant misregulation of cytokine signaling produces a more quiescent HSC, a disproportionate number of short-term progenitors, and hyperactivation of Pak1, leading to hematologic malignancies similar to those found in patients with X-linked lymphoproliferative disease. CD48 plays a vital role as an environmental sensor for regulating HSC and progenitor cell numbers and inhibiting tumor development. (Blood. 2011;118(1):80-87) IntroductionHSCs maintain lifelong blood production, but the mechanisms regulating them remain largely obscure. Although several genes have been identified that play key cell-autonomous roles in the HSC, [1][2][3][4] we still have few insights into the manner in which the BM milieu impacts HSC function. Under normal circumstances, the majority of HSCs reside in a quiescent state, with less than 5% in cycle at any given time. 5,6 Nevertheless, blood homeostasis is exquisitely effective, in that the progenitor pool and numbers of differentiated blood cells are maintained at a constant level. To ensure coordinated blood cell production, a sensitive feedback mechanism must be in place, so that the number of progeny are sensed by more primitive progenitors allowing for subtle regulation of the HSCs to generate more downstream cells only as needed. Moreover, under hematopoietic stress, the manufacture of differentiated cells is rapidly adjusted, marshaling increased output from both committed progenitors as well as HSCs. 7 When the loss of blood cells and committed progenitors is particularly complete, virtually all of the HSCs are transiently drafted, after which most of them return to quiescence to ensure long-term maintenance of the HSC pool. 6 CD48 was previously identified as broadly expressed on differentiated hematopoietic cells, but excluded from quiescent long-term HSCs (LT-HSCs). 3,8 CD48 is a GPI-linked member of the signaling lymphocyte activation molecule (SLAM) family of proteins. It can act as a ligand for SLAM member CD244 and, depending on the context, either inhibits or stimulates IFN␥ production from the target cell. 9-12 IFN␥ has previously been shown it to be a suppressor of hematopoiesis and at high levels it may lead to BM failure. 13 However, IFN␥ has also been shown to stimulate progenitor cell proliferation. [14][15][16] Recently, work from our laboratory has shown a lack of IFN␥ in vivo leads to a less proliferative HSC, whereas increasing IFN␥ increases HSC proliferation. 7 Because CD48 offered a context-dependent mechanism for the secretion of IFN␥, which impinges directly on HSCs, we sought to determine its role in maint...

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“…The dose-dependent induction of AIF was conserved across multiple probe sets and is consistent with the MRI data described above suggesting early vascular trauma. CD48, a plasma membrane immunoglobulin, is intimately involved in immune signaling and has been reported to act as a regulator that inhibits the malignant transformation of stem cells 18 . Finally, CCR1, a G-protein coupled plasma membrane receptor, is a known mediator of host immune response with a potential role in the induction of apoptotic cell death 19 .…”

Roles of CD48 in regulating immunity and tolerance

“…Boles et al observed altered distribution of monocyte and lymphocyte precursors in the bone marrow of CD48−/− [B6.129] mice and a reduced proliferative capacity of CD48−/− HSCs. Aged CD48−/− mice had an increased incidence of lymphoma, which correlated with upregulated Pak1 activity in CD19+ tumor cells but not in CD19+ cells from the spleen [122]. Whether altered hematopoiesis and increased incidence of tumors in CD48−/− [B6.129] mice is due to CD48 intrinsic effects, or interactions between 129- and B6-derived genes, remains to be determined.…”

The Src homology 2 protein Shb promotes cell cycle progression in murine hematopoietic stem cells by regulation of focal adhesion kinase activity

“…Utilizing the Shb knockout mouse [30], we find in the current study reduced bone marrow cell responsiveness to SCF-stimulation and elevated basal activity with respect to the FAK/Rac1/p21-activated kinase (PAK) signaling axis [11,28,31], proliferation defects in LT-HSCs during homeostasis, and an impairment in the long-term myeloid repopulating capacity of LT-HSCs. Unexpectedly, Shb is dispensable for stress hematopoiesis, and its loss results in diminished myelodepression in a non-competitive hematopoietic environment after genotoxic stress.…”

“…Signaling through FAK/Rac1/PAK has been implicated in LT-HSC and HPC cell cycle control, thus providing a mechanistic explanation for the observed differences in the LT-HSC cell cycle [10,11,28,31,43].…”

“…Rac1 has been implicated as an important regulator of LT-HSC and HPC cell cycle progression [11]. In addition, PAK has been demonstrated to regulate proliferation in several different hematopoietic lineages including mast cells and T cells [50,51] and PAK hyperactivation was recently linked to elevated LT-HSC proliferation in CD48 null mice [31]. …”