Role of the WT1 tumor suppressor in murine hematopoiesis

Abstract

The WT1 tumor-suppressor gene is expressed by many forms of acute myeloid leukemia. Inhibition of this expression can lead to the differentiation and reduced growth of leukemia cells and cell lines, suggesting that WT1 participates in regulating the proliferation of leukemic cells. However, the role of WT1 in normal hematopoiesis is not well understood. To investigate this question, we have used murine cells in which the WT1 gene has been inactivated by homologous recombination. We have found that cells lacking WT1 show deficits in hematopoietic stem cell function. Embryonic stem cells lacking WT1, although contributing efficiently to other organ systems, make only a minimal contribution to the hematopoietic system in chimeras, indicating that hematopoietic stem cells lacking WT1 compete poorly with healthy stem cells. In addition, fetal liver cells lacking WT1 have an approximately 75% reduction in erythroid blastforming unit (BFU-E), erythroid colonyforming unit (CFU-E), and colony-forming unit-granulocyte macrophage-erythroidmegakaryocyte (CFU-GEMM). However, transplantation of fetal liver hematopoietic cells lacking WT1 will repopulate the hematopoietic system of an irradiated adult recipient in the absence of competition. We conclude that the absence of WT1 in hematopoietic cells leads to functional defects in growth potential that may be of consequence to leukemic cells that have alterations in the expression of WT1. IntroductionWT1 was isolated as a tumor-suppressor gene on the basis of its deletion in a subset of patients with Wilms tumor, a pediatric cancer of the kidney. 1 In addition to its mutation in 5% to 10% of Wilms tumor patients, mutations of WT1 have been implicated in a variety of other cancers including mesotheliomas, desmoplastic round cell tumors, and leukemias. 1 WT1 encodes a protein of 52 to 54 kD, containing 4 zinc fingers of the Cys2 His2 class, that has been demonstrated to act as transcription factor. 1 Potential transcriptional targets for WT1 include a variety of growth factor and growth factor receptor genes. 1 An additional role for WT1 in RNA processing has also been proposed. 1 Many leukemias, including up to 80% of acute myeloid leukemias (AMLs), have been demonstrated to express WT1. [2][3][4][5][6][7][8][9][10] Mutations of WT1 have been found in approximately 5% to 10% of AMLs, similar to the level seen in Wilms tumors, and sporadically in a variety of other leukemias. [11][12][13][14][15][16][17][18] Manipulation of WT1 expression in leukemia cells results in alterations in differentiation and growth potential. [19][20][21][22][23][24][25][26][27][28] In the treatment of leukemia, expression of WT1 in the peripheral blood and bone marrow has been suggested to be an indicator of clinical relapse. Attempts have been made to correlate WT1 expression with progression of disease and prognosis in several types of hematologic malignancies. 3,[29][30][31][32][33][34][35][36][37] The clinical use of anti-WT1 cytotoxic T-lymphocytes (CTLs) for preferential destruction of WT1-expre...

The Wilms’ tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis

“…33,34 In addition, the GFP-reporter system will aid studies to understand the role of WT1 in normal development of kidney, 22 genital system 35 or other tissues 36,37 in which WT1 has an important role. Although Hastie and colleagues 38 previously generated WT1-LacZ reporter transgenic mice, a 40 consistent with the lack of its expression on HSCs. In contrast, our results show that WT1 is expressed in the immature (KLS) population of mouse leukemia induced by TEL/ PDGFbR þ AML1/ETO or p210 BCR/ABL.…”

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

“…A small subset of hematopoietic progenitor cells express WT1 (2-4) and progenitors lacking WT1 are less competitive during hematopoietic reconstitution in vivo (5), suggesting positive effects on proliferation and/or survival. Inducible deletion of WT1 in vivo in adult mice leads to rapid failure of erythrocyte formation (6).…”

Deregulation of the Wilms' tumour gene 1 protein (WT1) by BCR/ABL1 mediates resistance to imatinib in human leukaemia cells

“…3,4 In normal haematopoietic cells, WT1 is highly expressed in a subset of progenitors. [5][6][7][8][9][10] Analysis of lineage potential of haematopoietic progenitors from knockout mice demonstrates that WT1 is not critical for haematopoiesis, at least not in mice, 11 although murine progenitors lacking WT1 are less competitive during haematopoietic reconstitution in vivo, 12 suggesting positive effects of WT1 on proliferation and/or survival of haematopoietic cells.…”