High Expression of Lung Resistance Protein mRNA at Diagnosis Predicts Poor Early Response to Induction Chemotherapy in Childhood Acute Lymphoblastic Leukemia.

Prateek Bhatia,Deepak Bansal,Amita Trehan,Shet Masih,Neelam Varma

doi:10.7314/apjcp.2015.16.15.6663

Abstract

Treatment failure in leukemia is due to either pharmacokinetic resistance or cell resistance to drugs. Gene expression of multiple drug resistance protein (MDR-1), multidrug resistance-related protein (MRP) and low resistance protein (LRP) was assessed in 45 pediatric ALL cases and 7 healthy controls by real time PCR. The expression was scored as negative, weak, moderate and strong. The male female ratio of cases was 2.75:1 and the mean age was 5.2 years. Some 26/45 (58%) were in standard risk, 17/45(38%) intermediate and 2/45 (4%) in high risk categorie, 42/45 (93%) being B-ALL and recurrent translocations being noted in 5/45 (11.0%). Rapid early response (RER) at day 14 was seen in 37/45 (82.3%) and slow early response (SER) in 8/45 (17.7%) cases. Positive expression of MDR-1, LRP and MRP was noted in 14/45 (31%), 15/45 (33%) and 27/45 (60%) cases and strong expression in 3/14 (21%), 11/27 (40.7%) and 8/15 (53.3%) cases respectively. Dual or more gene positivity was noted in 17/45 (38%) cases. 46.5 % (7/15) of LRP positive cases at day 14 were in RER as compared to 100% (30/30) of LRP negative cases (p<0.05). All 8 (100%) LRP positive cases in SER had strong LRP expression (p=<0.05). Moreover, only 53.3% of LRP positive cases were in haematological remission at day 30 as compared to 100% of LRP negative cases (p=<0.05). Our study indicated that increased LRP expression at diagnosis in pediatric ALL predicts poor response to early treatment and hence can be used as a prognostic marker. However, larger prospective studies with longer follow up are needed, to understand the clinical relevance of drug resistance proteins.

Highlights

Acute lymphoblastic leukemia (ALL) is the commonest malignancy in children, comprising about 30-35% of all childhood cancers (Kaatsch et al, 2010)
Our study indicated that increased low resistance protein (LRP) expression at diagnosis in pediatric ALL predicts poor response to early treatment and can be used as a prognostic marker
A study by (Wanida et al, 2015), found polymorphisms in MDR1 gene to be associated with high risk pediatric ALL but others like (Madara et al, 2014) failed to find any relation between MDR1 polymorphism and pediatric ALL risk

Summary

Introduction

Acute lymphoblastic leukemia (ALL) is the commonest malignancy in children, comprising about 30-35% of all childhood cancers (Kaatsch et al, 2010). Treatment failure can be explained in part by pharmacokinetic mechanisms that reduce the time length or effective level of leukemic blast exposure to the drug, known as pharmacokinetic resistance. It can be partially explained by cell resistance to drugs (Pieters et al, 1997). Materials and Methods: Gene expression of multiple drug resistance protein (MDR-1), multidrug resistance-related protein (MRP) and low resistance protein (LRP) was assessed in 45 pediatric ALL cases and 7 healthy controls by real time PCR. Positive expression of MDR-1, LRP and MRP was noted in 14/45 (31%), 15/45 (33%) and 27/45 (60%) cases and strong expression in 3/14 (21%), 11/27 (40.7%) and 8/15 (53.3%) cases respectively. Larger prospective studies with longer follow up are needed, to understand the clinical relevance of drug resistance proteins

Methods

Results

Conclusion