Wilms tumor 1 expression: addressing the ‘elephant’ in MDS

‘How long do I have doc? ’ After pleasantries have been exchanged, a comprehensive medical history and physical exam have been performed, and a treatment plan has been discussed, we get to the ‘elephant in the room’, the reason a second opinion was sought: the question, pregnant with meaning, that any one of us would ask. The question is straightforward. In myelodysplastic syndromes (MDS), the answer is anything but. If we want to be simplistic, we could reflect on our patient’s World Health Organization (WHO) classification: perhaps our patient has MDS-excess blasts-1, and we estimate the survival to be roughly two years [1]. One step more complicated, and we invoke the international prognostic scoring system (IPSS), and now the revised-IPSS: in addition to a mild increase in blasts, our patient has anemia, profound thrombocytopenia, and aþ 8 karyotypic abnormality, and we estimate the survival to be approximately 1.5 years [2,3]. But, to loosely quote the singer Madonna, we are living in a molecular world, and we are molecular docs. It has become increasingly common to check for genomic mutations common to myeloid malignancies using any number of the standard next generation sequencing panels [4,5]. These limit results to the 20, or 30, or 40 known lesions found in the majority of patients with MDS, acute myeloid leukemia (AML), or myeloproliferative neoplasms. It turns out that expression of other genes matters as well. In this issue of Leukemia and Lymphoma, Mashima et al. explore the implications of Wilms tumor 1 (WT1) expression in MDS. WT1, historically associated with kidney cancer, is a tumor suppressor gene that encodes a zinc finger protein responsible for DNA transcription regulation. The gene was first described in 1990. WT1 messenger RNA was noted to be preferentially expressed in the kidneys and a subset of hematopoietic stem cells [6,7]. In myeloid malignancies, the WT1 gene was also found to be highly expressed and has been identified in some studies to even be a marker for minimal residual disease of AML post allogeneic hematopoietic cell transplantation (allo-HCT). In those studies, pre-transplant levels of WT1 expression also predicted for relapse post-HCT. To date, this has not been validated in patients with MDS [8, 9]. Mashima et al. examined 87 patients with MDS in whom peripheral blood WT1 messenger RNA expression was examined at diagnosis (n1⁄4 74) or monthly for at least three times post allo-HCT (n1⁄4 19). At the time of diagnosis of MDS, peripheral blood WT1 expression levels were associated with higher blast percentages (correlation coefficient, r1⁄4 .62, p< .01) and transfusion dependency (median WT1 level was higher in transfusion dependent vs independent patients, level1⁄4 8900 copies/lg RNA vs. 340 copies/lg RNA, p1⁄4 .011 respectively). In the post-HCT setting, relapses only occurred in patients with WT1 expression levels of >100 copies/lg RNA (n1⁄4 15). Thus, only those patients with higher WT1 expression were included in these analyses. Of the eight patients who relapsed in the post-transplant setting, seven had persistently high expression for at least two consecutive readings, while one patient had only one high WT1 level. Among patients with two consecutive readings of high WT1 expression, 77.8% of patients relapsed. Most (75%) of the relapsed patients had higher-risk MDS per IPSS (intermediate II or higher risk score), whereas 85.7% of patients who remained in remission post-transplant had intermediate I risk score, i.e. lower-risk disease [10]. Although the number of patients in this study was small in the post-transplant setting, persistently elevated WT1 expression levels may be a novel tool that could be used to predict relapse of MDS. With that in mind, WT1 expression