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.