CD99 triggers upregulation of miR‐9‐modulated PRDM1/BLIMP1 in Hodgkin/Reed–Sternberg cells and induces redifferentiation

Abstract

CD99 is a 32-kDa transmembrane glycoprotein that is encoded by the MIC2 gene. Our study was carried out to examine the role of CD99 in tumor progression of classical Hodgkin lymphoma (cHL). Here, we showed that lowly expressed CD99 protein in cHL cell lines and primary cHL cases correlates with the deficient expression of the positive regulatory domain 1 (PRDM1/ BLIMP1). In addition, cHL cell lines showed high levels of miR-9 expression. We determined that the upregulation of CD99 induced expression of transcription factor PRDM1, a master regulator of plasma-cell differentiation, which is also a target for miR-9-mediated downregulation. Indeed, inhibition of miR-9 also triggered upregulation of PRDM1 expression. Furthermore, overexpression of CD99 resulted in changed growth features and reorganization of actin cytoskeleton. As upregulation of CD99 led to a decrease in cHL diagnosis marker CD30 and CD15 and an increase in plasma-cell differentiation marker CD38 and the restoration of B-cell makers PAX5, CD79a and CD19, we suggest that downregulated CD99 leads to the prevention of plasma-cell differentiation in Hodgkin/Reed-Sternberg (H/RS) cells. Furthermore, these data indicate that CD99 may control miR-9 expression, which directly targets PRDM1. Altogether, these results reveal a CD99-miR-9-PRDM1 molecule axis in lymphomagenesis of cHL and suggest that upregulation of CD99 in H/RS cells induces terminal B-cell differentiation, which may provide a novel therapeutic strategies for cHL.The classical Hodgkin lymphoma (cHL) is a malignant lymphoma characterized by the presence of rare Hodgkin and Reed-Sternberg (H/RS) cells residing in a complex admixture of inflammatory cells. Although the nature of H/RS cells is still difficult to interpret, H/RS cells have evidence of abortive plasma-cell differentiation. 1 Recent published data showed that blockage of terminal B-cell differentiation may play a role in the pathogenetic mechanisms of B-cell lymphoma. [2][3][4] The positive regulatory domain 1 (PRDM1), also known as Blimp-1, is a transcriptional repressor that is a master regulator of terminal differentiation of B-cells into plasma cells. 5,6 It also plays a critical role in T FH and CD8 þ T-cell differentiation, 7,8 myeloid differentiation, 9 dendritic cell homeostatic development 10 and NK cell maturation. 11 PRDM1 is found in all plasma cells and in a small proportion of germinal center (GC) cells. 1 In the course of plasmacell differentiation, PRDM1 inhibits GC-B cell repressor BCL6, which can also repress expression of PRDM1. 12 MUM1/IRF4, expressed at high levels in plasma cells, coexpressed with PRDM1, is also critical for plasma-cell differentiation. 13 The consistent expression of MUM1 in H/RS cells demonstrates evidence of initial plasma-cell commitment and proposes a potential plasma-cell differentiation. 1 CD99, encoded by the MIC2 gene, is a human 32-kDa transmembrane glycoprotein, which is highly expressed in Ewing's sarcoma, anaplastic large-cell lymphoma, thymocytes and peripheral T cells. 14-17 CD9...

Deregulated FOX genes in Hodgkin lymphoma

“…Furthermore, two types of micro‐RNAs, miR34a and miR9 contributed to reduced levels of FOXP1 protein in HL cells as shown in B‐cells and glioblastoma cells, respectively (Rao et al, ; Gomez et al, ). Consistent with our data, miR9 plays a role in B‐cell development and is overexpressed in HL (Zhang et al, ; Huang et al, ; Leucci et al, ). Thus, deregulated micro‐RNAs may mediate deregulation of particular FOX gene activities in HL.…”

FOXO1 repression contributes to block of plasma cell differentiation in classical Hodgkin lymphoma

“…47,60 These results highlight the importance of gene regulatory mechanisms for PRDM1a repression in cHL and identify a central role for FOXO1 in this context.…”

Prognostic Biomarkers for Hodgkin Lymphoma

“…miR9-mediated down-regulation of PRDM1 has been demonstrated in HL [222]. Reinduction of PRDM1 expression after up-regulation of factors such as CD99 [225] or FOXO1 [226] was described. A prognostic role of PRDM1 has not been described; however, polymorphisms in PRDM1 have been found as risk factors for the development of secondary malignancies in pediatric HL patients [227].…”