Prognostic significance of receptor for hyaluronan acid-mediated motility (CD168) in acute pediatric leukemias – assessment of clinical outcome, post induction, end of treatment and minimal residual disease

Abstract

IntroductionThe extracellular matrix protein hyaluronan acid plays an active in role in tumor cell proliferation and invasion. Hyaluronan acid receptors, namely CD168 or the receptor for hyaluronan acid-mediated motility (RHAMM) and CD44 have been implicated in promoting malignancy. There is a lacuna in data on the expression of the receptor in pediatric leukemias.MethodsPediatric patients with acute leukemia who were diagnosed, treated and followed up in our center were enrolled. The bone marrow biopsies performed prior to treatment were subjected to immunohistochemical staining (54 biopsies: acute lymphoblastic leukemia – 45, acute myeloid leukemia – 9). Blast counts were carried out at diagnosis, end of the induction phase and end of chemotherapy, the minimal residual disease was assessed and follow up details were collected. Positivity was correlated with initial blast count, post-induction blast count, minimal residual disease and patient survival.ResultsThere was no correlation between the initial blast count and the percentage of blasts with RHAMM expression. The positive correlation between percentage of blasts expressing RHAMM and the post-induction blast count was moderate in acute myeloid leukemia (0.74) and mild in acute lymphoblastic leukemia (0.48). There was a statistically significant difference in RHAMM expression between the two minimal residual disease risk groups (p-value = 0.012) with a negative prognostic effect of RHAMM expression. Moreover, a negative prognostic effect of RHAMM expression was noted when patient survival was considered.ConclusionThis study shows that blasts in acute myeloid leukemia show more RHAMM positivity than those of acute lymphoblastic leukemia indicating the aggressive nature of this type of leukemia. In acute leukemias, patients with high percentages of RHAMM-positive blasts had more post-induction blasts, blasts in minimal residual disease and poorer prognosis.

Antigen Targets for the Development of Immunotherapies in Leukemia

“…CD168 or receptor for hyaluronan-mediated motility (RHAMM) was described as widely expressed LAA in AML, CML, and CLL [128,129]. A possible role of RHAMM as a biomarker for patient prognosis in acute pediatric leukemias was investigated revealing that patients with a high percentage of RHAMM-positive blast cells at the time of diagnosis had more blasts in minimal residual disease and a poorer prognosis [130]. By the in silico prediction of potential HLA-A*02-presented peptides from RHAMM, the peptide R3 (ILSLELMKL) was first characterized as a highly immunogenic CD8 + T-cell epitope in AML patients [83].…”

The cell cycle‐related genes RHAMM, AURKA, TPX2, PLK1, and PLK4 are associated with the poor prognosis of breast cancer patients

“…58 In patients with acute leukemia, the expression of RHAMM correlates with minimal residual disease and worse survival. 59 According to the results of Schütze and Wang, it is suggested that RHAMM has an important role in the invasiveness of tumor cells. Suggesting that due to its role in invasion RHAMM is a poor prognostic factor for patients.…”

“…On the other hand, in multiple myeloma, the expression of RHAMM was also associated with poor survival and osteolytic bone lesions 58 . In patients with acute leukemia, the expression of RHAMM correlates with minimal residual disease and worse survival 59 . According to the results of Schütze and Wang, it is suggested that RHAMM has an important role in the invasiveness of tumor cells.…”

Tumor-Tissue Expression of the Hyaluronic Acid Receptor RHAMM Predicts Histological Transformation in Follicular Lymphoma Patients

“…Furthermore, clinical trials with RHAMM peptide vaccination have demonstrated clinical and immunological responses in patients with acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS) [ 39 , 40 , 41 ]. Co-expression of RHAMM and CD44 was found to be predictive of poorer outcomes in DLBCL, and RHAMM expression was shown to be a negative prognostic marker in pediatric leukemia [ 42 , 43 ]. Otherwise, RHAMM’s role in lymphoid neoplasia, including FL, has not yet been elucidated.…”