Role of matrix metalloproteinase MMP-2, MMP-9 and tissue inhibitor of metalloproteinase (TIMP-1) in the clinical progression of pediatric acute lymphoblastic leukemia

Abstract

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− cancer stem cells (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 CD34+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, area under curve (AUC) of MMP-2 were (80.3%, 53.3% and 0.568, p = 0.404), and 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 CD34+CD38− CSCs were (78.9%, 73.3% and 0.855, p < 0.001). Increased TIMP-1 expression associated with the high-risk disease (p < 0.001). CD34+CD38− CSCs and MMP-2 overexpression associated with MRD at day-15, increased BM blast cell count at diagnosis and at day-15 ( p < 0.05). TIMP-1 overexpression is 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] could be potential independent diagnostic factors for pediatric ALL. Conclusion TIMP-1 and CD34+CD38− CSCs could be possible useful diagnostic markers for pediatric ALL. Also, TIMP-1 is a promising prognostic marker for poor outcome of the patients.