Monitoring WT1 mRNA to Detect AML Relapse

Sequential monitoring of Wilms’ tumor 1 (WT1) mRNA levels allows early detection of relapse among patients with acute myeloid leukemia (AML) who have achieved remission after chemotherapy or stem cell transplantation, according to researchers in Japan.

“Two consecutive high WT1 levels predicts relapse in the near future,” said senior study author Yoshinobu Kanda, MD, PhD, of the division of hematology, Saitama Medical Center and the department of medicine, Jichi Medical University, Tochigi-ken, Japan. That finding should therefore prompt a donor search for transplant-eligible, younger patients, he told Cancer Network.

“Preemptive treatment with azacitidine or other agents may be applied for such patients in the future,” Kanda said.

Among patients with two consecutive high WT1 levels (defined as more than 100 copies per µg of RNA), 75.8% had experienced hematologic relapse by 6 months. In contrast, only 7% patients without consecutive high-WT1 results experienced relapse.

The retrospective study assessed peripheral blood WT1 mRNA levels as a predictor of relapse among 55 patients with AML between 2012 and 2015. WT-1 level at diagnosis was predictive for outcome in myelodysplastic syndrome (MDS) but not AML, Kanda cautioned. The researchers believe the effect of WT-1 level at diagnosis disappeared following intensive induction chemotherapy among patients with AML, whereas WT-1 level after treatment became a prognostic biomarker of leukemic cells that are resistant to chemotherapy,.

WT1 gene mutations’ role in AML leukemogenesis are not yet completely understood but appear to involve both genetic and epigenetic evolution within tumor cells, and interaction between WT1 and the FLT3-ITD mutation, according to another recent study published in Blood. Like mutations in the FLT3, NRAS, KRAS and PTPN11 growth-signaling pathways, and IDH2 mutations, WT1 gene mutations predict transformation of MDS to AML.

A separate, larger recent analysis of WT1 levels in diagnostic bone marrow biopsies from 252 patients with AML by other researchers in Japan found that WT1 was positively associated with FLT-ITD and NPM1 mutations in cytogenetically normal AML, possibly suggesting that while WT1 expression correlates with prognosis, it does so indirectly because of its association with other, more strongly prognostic mutations. However, that study did not involve sequential WT1 monitoring after diagnosis.

“Because WT1 expression has correlated with known prognostic factors, the prognostic effect of WT1 levels could be misunderstood depending on the distribution of the collaborative mutations in each cohort,” cautioned the authors of the second study, based on their analysis of WT1 levels at the time of AML diagnosis.

The WT1 gene is involved in prenatal renal, ovarian, and testicular development and adult kidney function. WT1 protein is involved in cell growth, differentiation, and apoptosis. WT1 mutations were first described in Wilms tumor, a rare form of childhood kidney cancer. WT1 mutations and overexpression have also been implicated in AML and prostate cancer.