Proliferation Response of Leukemic Cells to CD70 Ligation Oscillates with Recurrent Remission and Relapse in a Low-Grade Lymphoma

Abstract

Interactions of the TNF-related cell surface ligand CD70 with its receptor CD27 provide a costimulatory signal in B and T cell activation. Functional CD70-CD27 interactions could contribute to lymphoma and leukemia progression. This possibility was studied using DNA microarrays on a unique case of low-grade lymphoma/leukemia characterized by recurrent cycles of acute leukemic phase alternating with spontaneous remission. Upon induction of the acute phase expression of CD70 and CD27 in the leukemic cells increased 38- and 25-fold, respectively. Coexpression of membrane CD70 and CD27 on the leukemic (CD5+CD19+) cells was maximal 2–3 days following initiation of the attack. Soluble CD27 in the patient’s serum was elevated during remission and further increased in the attack. Functional tests showed that neither anti-CD70 nor anti-CD27 Abs affect the rate of apoptosis. However, the anti-CD70 Ab specifically enhanced proliferation of the remission phase leukemic cells, whereas proliferation of the acute-phase counterparts that express higher level of membrane CD70 was unaffected. Hence, in this lymphoma/leukemia, membrane CD70 is presented on the leukemic cells in a responsive state during the remission and a nonresponsive state during the attack. Presumably, CD70 in its responsive state provides a costimulatory receptor for initiating the next acute phase while its nonresponsive state enables the remission.

The CD70-CD27 axis in oncology: the new kids on the block

“…Functional analysis showed that the CD70/CD27 interaction was also responsible for symmetric cell divisions, promoting the immature blast state and preventing myeloid differentiation [12]. The involvement of the CD70-CD27 axis in blastoid formation was also seen in a rare case of low-grade B cell lymphoma, where upregulation of CD70 and CD27 coincided with a highly increased gene expression of galactin 1 and TGF-ß receptor III, suggesting this could be implicated in the MEK and TGF-ß signaling pathway, respectively [80]. Related to this case, CD70 was higher expressed on the blastoid variant of mantle cell lymphoma, a clinically more aggressive form defined by a higher mitotic rate compared to the common mantle cell lymphoma [59].…”

Stroma-dependent apoptosis in clonal hematopoietic precursors correlates with expression of PYCARD

“…40 Both CD40 and CD70 are TNF-related surface receptors/ligands, well characterized in regard to their proapoptotic functions, particularly in lymphocytes. 41,42 In leukemia/ lymphoma cells, the activity of CD70 has been shown to depend upon the phase of the leukemia, 41 suggesting that the overall environment determines function. TP53, the most frequently mutated tumor suppressor gene described in humans, is centrally involved in apoptosis mediated by various insults.…”

High expression of CD40 on B-cell precursor acute lymphoblastic leukemia blasts is an independent risk factor associated with improved survival and enhanced capacity to up-regulate the death receptor CD95

“…Moreover, CD27 expression on malignant B cells has been found to oscillate during different phases of the disease as shown by elevated levels in the acute phase of low-grade lymphoma. 34 In addition, increased levels of soluble CD27 were detected in different B-cell malignancies, including ALL, which might suggest that shedding of the receptor may influence CD27 surface expression. 20 Such variability during the course of disease might be another reason why, despite its pertinent regulatory role in B-cell differentiation, cell growth, and death, 23,26,[35][36][37] cell surface expression of CD27 at diagnosis does not serve as a parameter for outcome.…”