AML1-ETO rapidly induces acute myeloblastic leukemia in cooperation with the Wilms tumor gene, WT1

Abstract

AML1-ETO,

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

“…This is not surprising considering the fact that LSAs are formed by genetic alterations (chromosomal translocations or gene mutations) that are causally involved in leukemogenesis. [50][51][52][53][54] Several LAAs have also been implicated in the multi-step leukemic transformation of hematopoietic progenitor cells, for example, ETO/MTG8, 55 hTERT 56 and the homeobox protein HOXA9. 57 The LAA WT1 may contribute to leukemogenesis by interfering with normal hematopoietic progenitor cell differentiation, which is considered as one of the first critical steps in the leukemic transformation of these cells.…”

“…57 The LAA WT1 may contribute to leukemogenesis by interfering with normal hematopoietic progenitor cell differentiation, which is considered as one of the first critical steps in the leukemic transformation of these cells. 16 In a transgenic mouse model, Nishida et al 50 also demonstrated the capacity of WT1 to induce leukemia in collaboration with the t(8;21) fusion protein AML1-ETO. 50 The leukemogenic role of WT1 has also been exemplified by its participation in the multiple cooperating events that underlie the progression of myelodysplastic syndromes to AML.…”

“…16 In a transgenic mouse model, Nishida et al 50 also demonstrated the capacity of WT1 to induce leukemia in collaboration with the t(8;21) fusion protein AML1-ETO. 50 The leukemogenic role of WT1 has also been exemplified by its participation in the multiple cooperating events that underlie the progression of myelodysplastic syndromes to AML. 58 Similar to WT1, downregulation of BMI1 has been observed upon normal differentiation of hematopoietic progenitor cells, whereas continuous overexpression accompanies their transformation into leukemic cells.…”

Anti-apoptotic quinolinate phosphoribosyltransferase ( QPRT ) is a target gene of Wilms' tumor gene 1 (WT1) protein in leukemic cells

“…In hematopoietic malignancy, WT1 is overexpressed in a majority of acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), correlated to poor clinical outcome (7)(8)(9)(10). WT1 interferes with differentiation of leukemic cell lines (11)(12)(13) and in mice, WT1 cooperates with the leukemia fusion protein AML1-ETO (RUNX1/RUNX1T1) to rapidly induce leukemia (14). Also various types of solid cancers show over-expression of WT1 (15).…”

Leukemia associated mutant Wilms’ tumor gene 1 protein promotes expansion of human hematopoietic progenitor cells

“…Mutations therefore might result in loss of WT1 function, due to haplo-insufficiency or to dominant negative effects, implying that wildtype WT1 acts as a tumour suppressor in leukemia. However, the frequent overexpression of wild-type WT1 in leukemias [9] and results from animal models [6,40] demonstrate an oncogenic role for wild-type WT1. These observations contradict WT1 being a tumour suppressor in leukemia.…”