Expression Of Ndrg1 In Mononuclear Cells From Children With Acute Leukemia: Correlation To Prognosis And Therapeutic Response

IntroductionNdrg1 (N-myc downstream regulated gene 1) has been implicated in the control of cell proliferation and differentiation. Many studies has confirmed that Ndgr1 gene expression was downregulated in a variety of solid tumors, and is now generally regarded as a novel tumor suppressor and tumor metastasis gene. However, there has been little clinical research on its possible role in childhood leukemia.ObjectivesTo study the expression of Ndrg1 gene in childhood leukemia and to explore possible correlations between expression and prognosis/therapeutic responses, thus documenting its role in prognostification and planning of individualized therapy for acute leukemia, especially for acute lymphoblastic leukemia.MethodsBM or peripheral blood mononuclear cells from 65 newly diagnosed cases of childhood acute leukemia and peripheral blood mononuclear cells from 12 healthy control children were isolated. Ndrg1 mRNA expression was determined by fluorescence quantitative PCR. In order to scale off the differences in initial RNA sampling and loading, the relative expression levels of Ndrg1 mRNA were represented by the ratio of Ndrg1 copy numbers to that of house-keeping gene GAPDH.Results1. Although Ndrg1 expression tended to be somewhat higher in peripheral blood mononuclear cells than that in bone marrow mononuclear cells from ALL, AML and control children, there were no statistically significant differences within each group (P＞0.05). Ndrg1 mRNA expression in acute leukemia collectively, ALL(41 cases) and AML(24 cases) groups was significantly lower than that of normal control (normalized ratios of Ndrg1 to GAPDH copy numbers were 0.19,0.17,0.19 and 0.41 respectively, (P＜0.05), though there was no statistically significant difference between ALL and AML groups(P=0.591).2. Ndrg1 expression was significantly lower in prednisone poor-responder (PRED-PR) ALL (13 cases) than in prednisone good-responder (PRED-GR) ALL (15 cases) (normalized ratios 0.15 and 0.29 respectively) (P=0.022).3. Similarly, Ndrg1 expression was significantly downregulated in high-risk ALL (17 cases) than that in lower-risk ALL(24 cases) (normalized ratios 0.13 and 0.25 respectively) (P=0.034).4. Ndrg1 expression was significantly downregulated in ALL-L3 (9 cases) than that in ALL-L1 and ALL-L2(totally 32 cases) (normalized ratios 0.12 and 0.25 respectively) (P＜0.009).ConclusionsOur research finding that Ndrgl expression was remarkably downregulated in childhood acute leukemia, including both ALL and AML, suggests that Ndrg1 might also be closely involved in leukemogenesis, as also documented previously in other human solid cancers. In addition, the negative correlation between Ndrg1 expression to increased clinical risk stratification and poor prednisone responsiveness in acute childhood ALL strongly indicates that Ndrg1 downregulation is a novel unfavorable prognostic indicator for ALL patients and endows ALL patients with poor therapeutic response and survival. Interestingly, remarkably low expression of Ndrg1 in ALL-L3, as being expected from its close association to N-Myc oncogene, which is frequently implicated by chromosome translocations involving immunoglobulin genes, might be related to rapid leukemic cell proliferation and rapid clinical progression in case of ALL-L3.