Role of Matrix Metalloproteinase MMP-2, MMP-9 and Tissue Inhibitor of Metalloproteinase (TIMP-1) in Clinical Progression of Pediatric Acute Lymphoblastic Leukemia

Abstract

Background: Matrix metalloproteinases (MMPs) play a crucial role in cancer progression and metastasis, however their role in pediatric Acute lymphoblastic leukemia (ALL) is still unrevealed.Methods: The diagnostic, prognostic and predictive value of tissue inhibitor of metalloproteinase (TIMP-1), MMP-2, MMP-9 and CD34+CD38- CSCs were assessed in bone marrow (BM) samples of 76 ALL children using Flow Cytometry analysis. Results: There was a significant increase in TIMP-1 [1.52 (0.41-10) versus 0.91(0.6-1.12); respectively, P<0.001], and CSCs CD84+CD38- [1 (0.03-18.6) versus 0.3 (0.01-1.1), P<0.001] expression in ALL patients compared to controls. While there were no significant differences regarding MMP-2 and MMP-9 expression between the two groups. The sensitivity, specificity, AUC of MMP-2 were (80.3%, 53.3% and 0.568, P=0.404), and that of MMP-9 were (53.9%, 40% and 0.660, P=0.053). While that of TIMP-1 were (78.9%, 100% and 0.892, P<0.001), and that of CSCs CD34+ CD38- were (78.9%, 73.3% and 0.855, P<0.001). There was a significant association between MMP-2 overexpression and MRD at day-15, increased BM blast cell count at diagnosis and at day-15, (P=0.020, P=0.047 and P=0.001). Increased TIMP-1 expression associated with the high-risk disease (P<0.001), increased BM blast cell count at diagnosis and at day-15 (P=0.033 and P=0.001), as well as MRD at day 15 and day 42 (P<0.001 for both). CD34+CD38- CSCs associated with MRD at day-15, increased BM blast cell count at diagnosis and at day-15 (P=0.015, P=0.005 and P=0.003). TIMP-1 overexpression associated with shorter DFS and OS rates (P=0.009 and P=0.048). Multivariate logistic regression analysis showed that both TIMP-1 [OR: 4.224, P=0.046], and CD34+CD38- CSCs [OR: 6.873, P=0.005] are independent diagnostic factors for pediatric ALL.Conclusion: TIMP-1 and CD34+CD38- CSCs could be useful independent diagnostic markers for pediatric ALL. Also, TIMP-1 is a promising prognostic marker for poor outcome of the patients.