Prognostic Value and Correlation Between WT1 Overexpression and NPM1 Mutation in Patients with Acute Myeloblastic Leukemia

Abstract

Background. Acute myeloblastic leukemia (AML) with NPM7 mutation amounts to 30 % of all AML and is characterized by good prognosis with the exception of cases with FLT3-/TD mutation. Despite the good prognosis, the likelihood of relapses in patients with NPM7 mutation may significantly differ. Thus, the estimation of the minimal residual disease (MRD) after chemotherapy and during follow-up is becoming increasingly important. This approach will make it possible to predict the sensitivity of a tumoral clone to chemotherapy. Aim. To evaluate the prognostic value of highly specific marker (NPM7 mutation) and non-specific marker (WT1 overexpression) of MRD, as well as to identify the correlation between the levels of NPM7 and WT7 at different stages of therapy and in the follow-up period. Materials & Methods. The research included 14 patients with AML. All patients had the NPM7 mutation and WT7 overexpression: 50 % of patients had additional molecular markers (BAALC overexpression, FLT3-/TD, DNMT3A, and MLL mutations). Real-time PCR was used for long-term monitoring of WT7 expression levels and NPM7 mutation. Results. The median decrease of NPM7 levels after the induction therapy was 3 log. All patients had relapses, NPM7 mutation, and lower rates of OS/RFS, which significantly correlated with prognostically negative molecular markers. There were no statistically significant differences in RFS in groups with the decrease of WT7 expression level < 2 log and ≥ 2 log on day 28 of treatment. At the same time, the decrease of WT7 expression by > 2 log was associated with significant differences in early relapses, which correlated with the decrease of NPM7 levels (> and < than 3 log) is revealed. RFS rates were higher in patients with WT7 expression level of < 100 per 10<sup>4</sup> copies ABL on day 28 and WT7 of < 250 per 10<sup>4</sup> copies ABL on day 14 of treatment. WT7 expression was significantly lower on days 14 and 28 in patients with NPM7 decrease of > 3 log on day 28. The decrease in WT7 expression of < 100 per 10<sup>4</sup> copies ABL on day 28 was more common in patients with isolated NPM1 mutation, compared to patients with additional negative molecular markers. Conclusion. The decrease in NPM1 levels after the induction therapy may serve as reliable prognostic marker of RFS and OS rates. New correlation between the degree of NPM1 reduction and the presence of additional molecular markers was established. Highly specific (NPM1 mutation) was shown to be more specific compared to non-specific markers ( WT1 overexpression). The research showed the predictive value of a lower limit level of WT1 on day 28 of treatment (100 per 10<sup>4</sup> copies ABL), and for the first time, the importance of the early assessment WT1 expression reduction on day 14 of induction therapy.

WT1 Gene Overexpression in Differential Diagnosis of Ph-Negative Myeloproliferative Disorders

“…Предполагается, что WT1 может влиять на пролиферативный потенциал лейкозных клеток, их жизнеспособность и выступать в роли онкогена при развитии гематологических опухолей [12]. Прогностическое значение исходного уровня гена WT1 при ОМЛ четко не определено, при этом динамика уровня его экспрессии активно используется для оценки минимальной остаточной болезни и прогнозирования отдаленных результатов терапии [13][14][15]. Клиническое значение гиперэкспрессии гена WT1 при других миелоидных опухолях, в т. ч. при Phнегативных миелопролиферативных заболеваниях (МПЗ), активно изучается.…”

Efficacy of Chemotherapy in Acute Leukemia Patients Resistant to Previous Standard Treatment According to the Series Measurement of WT1 Gene Expression

“…Факт повышенной экспрессии гена WT1 при острых лейкозах (ОЛ) был установлен вскоре после его открытия [5,6], а повышенный интерес исследователей к этому гену объясняется несколькими моментами. Во-первых, уровень гена WT1 неплохо отражает экспрессию специфических слитных генов [1,[7][8][9][10][11][12], причем темп его нарастания и снижения значительно опережает последние [1]. Во-вторых, изучение уровня экспрессии гена WT1 в мо-лекулярной биологии дает возможность количествен-ного определения бластных элементов в тестируемых тканях [1,4,9,13].…”

“…До настоящего времени такой подход чаще ис-пользовался для диагностики минимальной оста-точной болезни после трансплантации гемопоэтиче-ских стволовых клеток (ТГСК) [1,4,[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22], а также для раннего распознавания рецидивов ОЛ [4,9,[23][24][25][26][27][28][29]. В то же время исследований, посвященных оценке эффективности индукционных курсов химиотерапии, недостаточно [4,14,[30][31][32][33][34][35][36][37].…”