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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 43  |  Issue : 1  |  Page : 38-43

Wilms’ tumor gene 1 expression can predict sudden disease progression to blast crisis in patients with chronic myeloid leukemia receiving imatinib therapy


1 Hematology Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
2 Clinical Pathology Department, Military Medical Academy, Cairo, Egypt

Date of Submission01-Feb-2018
Date of Acceptance25-Mar-2018
Date of Web Publication3-Aug-2018

Correspondence Address:
Mohamed A.M El-Menoufy
Hematology Department, Medical Research Institute, Alexandria University, Alexandria 21561
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejh.ejh_5_18

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  Abstract 


Background The Philadelphia chromosome is the hallmark of chronic myeloid leukemia (CML). As the disease progresses to accelerated phase and blast crisis (BC), clonal evolution may occur with the emergence of additional chromosomal abnormalities. Wilms’ tumor 1 gene (WT1) plays an important role in leukemogenesis, and its expression could represent a useful molecular marker of hematological malignancies.
Aim The aim of this study was to evaluate WT1 expression and compare its kinetics with that of BCR-ABL1 expression in peripheral blood of patients with CML, to explore the utility of WT1 as an alternative marker for prediction of early disease progression and sudden transformation to BC.
Patients and Methods A total of 49 newly diagnosed patients with CML, and 20 normal individuals as controls were enrolled in this study. WT1 and BCR-ABL1 expression was evaluated by quantitative real-time PCR.
Results There was significant correlation between the expression of WT1 and BCR-ABL1 only at diagnosis and after 3 and 6 months of therapy. At 12 months of follow-up, an increase in %WT1 associated with low BCR-ABL1 was noticed in two of cases. One case suddenly progressed to BC at 18 months, and the other case showed emergence of clonal chromosome abnormality (+8) and progressed to accelerated phase.
Conclusion Our results suggested that serial assessment of WT1 transcript level in patients with CML may be a useful marker for predicting early and sudden disease progression into advanced stages.

Keywords: BCR-ABL1, chronic myeloid leukemia, sudden blast crisis, Wilms’, tumor gene 1


How to cite this article:
El-Menoufy MA, Ahmed MA. Wilms’ tumor gene 1 expression can predict sudden disease progression to blast crisis in patients with chronic myeloid leukemia receiving imatinib therapy. Egypt J Haematol 2018;43:38-43

How to cite this URL:
El-Menoufy MA, Ahmed MA. Wilms’ tumor gene 1 expression can predict sudden disease progression to blast crisis in patients with chronic myeloid leukemia receiving imatinib therapy. Egypt J Haematol [serial online] 2018 [cited 2019 Dec 8];43:38-43. Available from: http://www.ehj.eg.net/text.asp?2018/43/1/38/238544




  Introduction Top


The Philadelphia (Ph) chromosome is the hallmark of chronic myeloid leukemia (CML). It represents the fusion of BCR-ABL gene (oncogene) that encodes a deregulated, constitutively active tyrosine kinase that promotes cell proliferation and survival and mediates leukemogenesis through activating different pathways, such as JAK/STAT, MYC, RAS/RAF/MEK/ERK, and MAPK [1]. Typically, CML evolves through three clinical phases: an initial chronic phase (CP) in which the disease is usually diagnosed, followed by a transient, ill-defined accelerated phase (AP), and a terminal blastic phase or blast crisis (BC), which behaves like an acute leukemia [1],[2]. As the disease progresses to AP and BC, clonal evolution (CE) may occur with the emergence of additional chromosomal abnormalities [3],[4]. CE is thought to reflect the genetic instability of the highly proliferative CML progenitors, and it is considered one of the criteria for defining AP of CML (CML-AP) [5]. It occurs in ∼30% of patients with CML-AP and 80% of patients with CML-BC [6]. It has been previously reported that mutations may occur more frequently among patients with CE [7].

Progression to BC is characterized by increased cell proliferation with arrested cell differentiation and resistance to apoptosis [8]. Furthermore, it represents a disturbing event as it remains the major obstacle to successful treatment of patients with CML and would reduce the high curative potential of allogeneic stem cell transplantation performed in patients present in the CML-CP.

A sudden onset of blast crisis CML (CML-SBC) was defined as BC developing after a documented complete cytogenetic response (CCyR) in the immediately preceding bone marrow analysis and within 3 months of a normal complete blood count in a patient receiving therapy [9],[10]. It has been occurring unexpectedly in patients in complete hematologic remission during imatinib (IM) therapy [11],[12].

The Wilms tumor 1 gene (WT1) encodes a transcription factor that is important in the regulation of cell growth, apoptosis, and differentiation [13],[14],[15]. It has been shown that its expression level is overexpressed or mutated in different forms of acute leukemia, myelodysplastic syndrome, and CML-BC and plays a prognostic role in these diseases [16],[17],[18]. Therefore, WT1 expression could thus represent a universal molecular marker of hematological malignancies [19],[20]. However, the precise mechanism through which WT1 may play a role in leukemogenesis and disease progression has remained elusive [21],[22].

Apart from BCR-ABL analysis, there is a high heterogeneity regarding the markers and techniques used to monitor CML progression to advanced stages (AP and BC). Unfortunately, in rare instances, the BCR-ABL expression level remains low or even undetectable when measured immediately before CE or sudden progression to BC [9]. Therefore, an alternative sensitive assay is essentially required for detection of an early threatening progression, in these rare conditions, and the start of early therapeutic intervention.

In the present study, we evaluated WT1 expression and compared its kinetics with that of BCR-ABL1 expression in peripheral blood (PB) of patients with CML, to explore the utility of WT1 as an alternative marker for prediction of early disease progression and CML-SBC.


  Patients and methods Top


This study was carried out on 49 patients with CML. They were 28 males and 21 females, with mean age of 45 years. The patients were chosen from outpatient clinic or inpatients of Hematology Department of Medical Research Institute Hospital, Alexandria University, and Mostafa Kamel Military Hospital.

All patients were newly diagnosed or soon after start of therapy when BCR-ABL was still near to pretreatment level. All patients were in CP and had received the standard daily IM dose of 400 mg. Diagnosis of CML cases was based on clinical and laboratory assessment according to Baccarani et al. [23].

The definition of chronic, accelerated, and blastic phases was based on the criteria of the WHO [2],[5].

PB samples from 20 normal healthy volunteers were included in the study to define the normal range of WT1 expression.

PB samples from all patients with CML were analyzed for BCR-ABL1 and WT1 expression at diagnosis; thereafter, they were regularly monitored for at least 24 months starting from the initiation of IM therapy. Hematological status was assessed monthly; BCR-ABL1 levels in PB were assessed after 3, 6, 12, 18, and 24 months, in parallel with WT1 levels. Marrow cytogenetic analysis to determine Ph chromosome status and any additional chromosomal changes was performed every 6 months.

Statistical methods

Statistical analysis of the present study was conducted using mean, median, the Student t-test, and the χ2-test. Spearman rank correlation was used for correlations between continuous parameters. The P value was then obtained from all these tests: P value more than 0.05 was considered nonsignificant, P value 0.05 or less was considered significant, and P value 0.001 or less was considered highly significant. Statistical analysis was carried out using the software package SPSS version 24.0 (SPSS IBM Corporation, New York, USA).

Consent

Informed consent was obtained from all patients included in the study, according to the ethical guidelines of the Medical Research Institute Alexandria University (Appendix 1, Informed Written Consent for patient participation in a Clinical Research 2011). The study was conducted in accordance with the local ethical committee, and informed consent was obtained from all patients included in the study.


  Methods Top


PB samples were collected in sterile EDTA tubes. Mononuclear cells were isolated using Ficoll–Hypaque density centrifugation. The total RNA was extracted using Qiagen RNA Blood Mini kit (Qiagen, Hilden, Germany) according to the instructions of this kit. Complementary DNA was then synthesized using complementary DNA synthesis kit (Applied Biosystems, Foster City, CA, USA) according to the manufacturer’s instructions.

Quantitative estimation of BCR-ABL1 and WT1 was performed by real-time quantitative PCR (RQ-PCR) using the Light Cycler Instrument (Roche, Mannheim, Germany) as previously described [24],[25],[26]. The relative quantification of both markers was carried out using ABL1 as reference gene for normalizing real-time data. Results were expressed as percentage as follows: number of mRNA of target gene divided by the total number of ABL1 (reference gene) and multiplied by 100.


  Results Top


The demographic characteristics of the patients with CML at diagnosis are summarized in [Table 1], with no significant relation between the patient’s age, sex, hemoglobin level, total leucocytic count, platelet count, Sokal scoring, and WT1 expression level.
Table 1 Characteristics of the patients with chronic myeloid leukemia included in the study (at diagnosis)

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Wilms’ tumor gene 1 expression in controls and patients with chronic myeloid leukemia at diagnosis

The median expression level of WT1 in normal individuals was 0.084% (range: 0.00–1.270).

Although the median expression level of WT1 in patients with CML at diagnosis was 1.008% (range: 0.001–4.198), which was higher when compared with the normal individuals, yet it did not reach the level of significance (P=0.541).

Correlation of Wilms’ tumor gene 1 and BCR-ABL1 expression at diagnosis and during follow-up

  1. At diagnosis and after 6 months of IM therapy, there was highly significant correlation between WT1 and BCR-ABL1 expression (P=0.001 and 0.009, respectively) ([Figure 1] and [Figure 2]). However, at 12 months of therapy and onward, no correlation was found between BCR-ABL1 and WT1 expression.
    Figure 1 Correlation between %WT1 and %BCR-ABL1 expression levels at the time of CML diagnosis. CML, chronic myeloid leukemia; WT1, Wilms’ tumor gene 1.

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    Figure 2 Correlation between %WT1 and %BCR-ABL1 expression levels at 6 months of starting imatinib therapy. WT1, Wilms’ tumor gene 1.

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  2. There was a significant reduction in WT1 in patients with CML on IM therapy in comparison with newly diagnosed patients with CML (P=0.0001).


Response to imatinib therapy and correlation of Wilms’ tumor gene 1 and BCR-ABL1 in responders and nonresponders

During follow-up, the responses to treatment were defined according to European LeukemiaNet recommendations in 2013 [27]. A total of 42 patients achieved major molecular responses and/or CCyR and seven patients failed to respond to IM therapy (primary failure). Four patients lost their complete hematological response, CCyR, and/or major molecular responses (secondary failure). There was no significant correlation between WT1 and BCR-ABL1 expression in patients resistant to IM therapy, either primary or secondary resistance (P=0.571).

At 24 months of follow-up, the median expression level of WT1 in the remaining responders (38 patients) was 0.334%, with no significant correlation with BCR-ABL1 expression (P=0.921).

Clonal evolution and progression to blastic phase

During follow-up, the disease in the four patients with secondary IM resistance run a progressive course to advanced-stage CML (one patient in AP and three patients in BC). At 12 months of follow, an increase in WT1 associated with decreasing BCR-ABL1 expression was noticed in two of these cases (case no. 35 and 43). A sudden BC was observed at 18 months in case no. 35 ([Figure 3]). At the last follow-up, the case number 43 showed additional clonal chromosome abnormality (+8) (CE) and progressed to AP ([Figure 4]). In another one patient (case no. 34), increased WT1 expression associated with low BCR-ABL1 expression was noticed. Whether this will be followed by CE or progression to advanced stage CML has to be seen.
Figure 3 Case number 35: the log percentage expression of BCR-ABL1/ABL1 and WT/ABL1 versus the time in months. This patient showed a sudden blast crisis at 18 months of therapy. A rise in %WT1 expression started at 12 months, whereas %BCR-ABL1/ABL1 was still declining until 18 month when it started to rise. WT1, Wilms’ tumor gene 1.

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Figure 4 Case number 43: the log percentage expression of BCR-ABL1/ABL1 and WT/ABL1 versus the time in months. This patient showed a clonal evolution (trisomy 8) and progressed to AP at 18 months of therapy. A rise in %WT1 expression started at 12 months whereas %BCR-ABL1/ABL1 was still declining until 18 month when it started to increase, and its level was still low. AP, accelerated phase; WT1, Wilms’ tumor gene 1.

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  Discussion Top


Based on previous reports that assessment of WT1 expression might be beneficial for follow-up of patients with CML [28],[29], we performed correlation studies of BCR-ABL1 and WT1 expression in 49 patients undergoing IM therapy. Our results showed good correlation between them only at diagnosis and at both 3 and 6 months of IM therapy. However, this significant correlation completely disappeared thereafter at 12, 18, and 24 months of therapy. This finding was different from that of previous studies [20],[28],[30], which reported strict parallel kinetics of BCR-ABL1 and WT1 expression in PB of patients with CML. Hajizamani et al. [31] did not find significant correlation between WT1 and BCR-ABL1 in newly diagnosed patients with CML. Uzunel and Ringdén [32] demonstrated a poor correlation between WT1 and BCR-ABL levels in most patients after transplant. This difference may be related to the inclusion of AP and blastic-phase patients, the time point of analysis, and WT1 evaluation in bone marrow samples.

Useful information was obtained from our results, especially in advanced-stage CML, as in case number 35 that suddenly progressed to BC, the increase of WT1 that preceded the progression was associated with low BCR-ABL1 expression. This was in accordance with the Schnittger et al. [33] who found that the increase in WT1 expression preceded the transformation to BC, whereas BCR-ABL1 expression was stable. Similarly, in another patient in our study (case no. 43), the increase in WT1 expression in parallel to low BCR-ABL1 expression levels seemed to be associated with early emergence of additional chromosomal aberration (trisomy 8), that is, CE and sudden progression to AP, whereas the low level of BCR-ABL1 expression could not discriminate between responders and nonresponders [29]. In this regard, Schnittger et al. [33] also reported two CML cases in which WT1 expression was increasing despite very low or even undectable BCR-ABL1 levels and both cases revealed Ph-negative aberrant chromosomal abnormalities (CE). In another patient (case no. 34, not shown), increasing WT1 expression associated with low BCR-ABL expression was noticed. Whether this will be followed by CE or progression to advanced stage CML needs to be seen.

The mechanisms and the molecular events involved in CML progression to advanced stages have not been completely explained yet [8],[34] They may involve BCR-ABL1–dependent mechanisms, such as ABL kinase domain mutations [35], BCR/ABL1 overexpression [36], and various BCR/ABL1–independent mechanisms [37]. Hamilton et al. [38] demonstrated that CML stem cells are not dependent on BCR-ABL kinase activity for their survival.

The observation that WT1 overexpression is associated with low BCR-ABL expression in SBC raised the question as to whether WT1 plays a direct role in CE and sudden blast transformation independent on BCR-ABL1. It is highly plausible that in CML-CP, BCR-ABL1-independent preexisting genetic lesions may function as ‘amplifiers’ of a genetically unstable phenotype and thereby predispose CML to blastic transformation by affecting the proliferation, differentiation, survival, and/or genomic stability of the leukemic stem and progenitor cells [8].

Schmidt et al. [39] suggested the occurrence of BCR-ABL1-independent gene mutations affecting several genes such as DNMT3A, RUNX1, and TET2 in Ph-negative and Ph-positive clones of patients with CML may be considered as important cofactors in the CE of CML. They revealed one DNMT3A mutation in Ph-negative cells that was also present in Ph-positive cells at diagnosis, implying that the mutation preceded the BCR-ABL rearrangement.

A deregulated WT1 will affect its important role in the regulation of mitotic check point and the genomic stability [40], resulting in inefficient and unfaithful DNA repair. DNA damage and subsequent emergence of mutations and CE may drive the disease with high possibility to progression into advanced stage.

Recently, Hajizamani et al. [31] and Zhang et al. [41] suggested a role of WT1 in activation of the signaling pathways involved in CML pathogenesis. WT1 activates MAPK JAK/STAT pathway-related genes, which promote proliferation and survival of a cell. Furthermore, WT1 upregulation plays an important role in tumorigenesis and progression of leukemia through Wnt/β-catenin pathway [42] and increases ABCB1 expression [43]. ABCB1 is involved in drug resistance in CML [44].

However, more recent work has revealed a new role for WT1 mutation in the deregulation of epigenetic programs in leukemic cells through its interaction with TET2 protein and mediating dysregulated DNA hydroxymethylation [45],[46]. These observations have given rise to an enhanced understanding of the complexity of the pathogenic role of this protein in leukemogenesis [21]. Moreover, Nishida et al. [47] indicated that AML-ETO gene, which is recognized as a common chimeric gene in acute myeloid leukemia (AML) with t(8;21), mediated its leukemogenesis effect in cooperation with WT1 expression, as AML-ETO could not induce AML by itself.

In this respect, Singh et al. [48] reported a case of AML with AML1-ETO fusion protein associated with BCR-ABL transcripts, and the bone marrow showed extensive basophilia. It might represent a case of CML that underwent CE and progression to AML. This may point to a possible role of WT1 transcript in the pathogenesis of sudden CML progression to BC.

Based on our findings, a multicenter trial should be initiated to define the role of WT1 in the pathogenesis of sudden transformation of CML into BC, and its usefulness in monitoring patients with CML under therapy who will possibly progress into SBP as compared with others, using a completely standardized real-time WT1-RT-PCR protocol. Serial quantitative testing for WT1 expression might be useful to identify the sudden evolution and progression of CML months before hematological and clinical signs of this disease.


  Conclusion Top


Our results suggests that serial assessment of the WT1 transcript level in patients with CML may be a useful marker for predicting early and sudden disease progression into advanced stages even in patients with low BCR-ABL1 expression.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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