Abstract
Background: Abnormal high ecotropic viral integration site 1 (EVI1) expression was recognized as a poor prognostic factor in acute myeloid leukemia (AML) patients. However, its prognostic impact in B cell precursor acute lymphoblastic leukemia (BCP-ALL) remains unknown.
Procedures: A total of 176 pediatric Ph-negative BCP-ALL patients who received at least 1 course of chemotherapy and received chemotherapy only during follow-up were retrospectively tested EVI1 transcript levels by real-time quantitative PCR at diagnosis and survival analysis was performed. Clinical and EVI1 expression data of 129 pediatric BCP-ALL patients were downloaded from the therapeutically applicable research to generate effective treatments (TARGET) database for validation.
Results: In our cohort, the median EVI1 transcript levels were 0.33% (range, 0.0068-136.2%), and 0.10% was determined as the optimal cutoff value for patient grouping by receiver operating characteristic curve. Low EVI1 expression (<0.10%) was significantly related to lower 5-year relapse-free survival (RFS) and overall survival (OS) rates (P =0.017 and 0.018), respectively. Multivariate analysis showed that EVI1<0.10% was an independent adverse prognostic factor for RFS and OS. TARGET data showed that low EVI1 expression tended to be related to a lower 5-year OS rate (P =0.066).
Conclusions: Low EVI1 expression at diagnosis may predict poor outcome in pediatric Ph-negative BCP-ALL patients receiving chemotherapy.
Keywords : Pediatric B cell precursor acute lymphoblastic leukemia; Ph-negative; EVI1 expression; At diagnosis; Prognosis
1. Introduction
The ecotropic viral integration site 1 (EVI1) gene was first recognized as a common locus of retroviral integration in murine myeloid leukemia models and found to be critical in transformation of murine hematopoietic cells.1,2Subsequent studies demonstrated that EVI1 is a hematopoietic stemness and transcription factor, which plays a pivotal role in the regulation of hematopoietic stem cell (HSC) self-renewal and myeloid leukemogenesis.3-5 EVI1 is located on chromosome 3q26, and rearrangements on chromosome 3q26 often activate EVI1 expression which could be seen in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myeloid leukemia (CML).6In addition, overexpression of EVI1 also occurs in patients without 3q26 abnormalities.7,8 Importantly, several studies have uniformly demonstrated that high EVI1 expression confers a poor prognosis to AML.9-12 We once evaluated adult AML patients with intermediate cytogenetic risk receiving chemotherapy (ICR-AML) and found that high EVI1 expression was an independent negative prognostic indicator.13
Compared to myeloid malignancies, the expression pattern and the role of EVI1 in lymphoid malignancies are far less investigated. EVI1 mRNA expression was confirmed in the majority of analyzed lymphoid cell lines and primary samples from patients with pediatric and adult acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) by real-time quantitative PCR (RQ-PCR).14-17 The microarray data showed that the range of EVI1 expression levels in pediatric ALL is much smaller than that in AML.18 The in vitro and mice transplantation study demonstrated that EVI1 contributes to the leukemogenic potential and apoptosis resistance of ALL cells, which implied its link to poor prognosis.14Whereas in CLL, EVI1 was assigned tumor suppressor-like functions because of a negative interaction with the TCL1A oncogene to impact cell survival and clinical outcomes.17 The effect of EVI1 expression on outcomes of patients with ALL could only be obtained by clinical cohort studies. However, it remains absent to date.
In the present study, the bone marrow samples collected from 176 newly diagnosed pediatric Ph-negative B cell precursor ALL (BCP-ALL) patients were performed RQ-PCR to detect EVI1 transcript levels, and the survival analysis was performed to investigate its prognostic role. We further validated the result by the RNA-seq data of ALL Expansion Phase 2 Project which downloaded from the Therapeutically Available Research to Generate Effective Treatments (TARGET, http://ocg.cancer.gov/programs/target) database.