Downregulation of Wilms’ tumor gene (WT1) is not a prerequisite for erythroid or megakaryocytic differentiation of the leukemic cell line K562

Svedberg, Helena; Chylicki, Kristina; Gullberg, Urban

doi:10.1016/s0301-472x(99)00038-7

Cited by 13 publications

(10 citation statements)

References 27 publications

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“…32,41,45 Our results give no support for an impaired differentiation of human hematopoietic progenitors due to forced expression of WT1. However, this might be the result of selection against cells expressing high levels of WT1 (not dividing during culture).…”

Section: Figurementioning

confidence: 60%

Forced expression of the Wilms tumor 1 (WT1) gene inhibits proliferation of human hematopoietic CD34+ progenitor cells

2001

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The Wilms tumor gene (WT1) encodes a zinc-finger containing transcription factor present in primitive hematopoietic progenitor cells. WT1 is also highly expressed in most cases of acute myeloid leukemia. Moreover, WT1 can interfere with induced differentiation of leukemic cell lines. These data suggest a function of WT1 in the maintenance of a primitive phenotype and a role in leukemogenesis by interfering with differentiation, prompting us to investigate its function in human hematopoietic progenitor cells. By retroviral transfer, human CD34 + cord blood progenitor cells were transduced with a vector encoding either of two splicing variants of WT1, with or without the KTS insert in the zinc-finger domain, linked to expression of green fluorescent protein (GFP) via an internal ribosomal entry site. When compared to cells transduced with vector containing GFP only, WT1 expressing cells showed strongly reduced colony formation in methylcellulose and inhibited proliferation in suspension culture, with no apparent reduction in viability. Cell cycle phase distribution was not affected by WT1 expression. No signs of impaired differentiation, as judged by the surface markers CD11b, CD14 and glycophorin were detected. In contrast to the results with human CD34 + progenitor cells, the proliferation of murine bone marrow cells was not significantly affected by WT1, consistent with previous data. We conclude that forced expression of WT1 in highly enriched human hematopoietic progenitor cells leads to strong anti-proliferative effects but is compatible with induced maturation of these cells. Leukemia (2001Leukemia ( ) 15, 1914Leukemia ( -1922

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Section: Figurementioning

confidence: 60%

Forced expression of the Wilms tumor 1 (WT1) gene inhibits proliferation of human hematopoietic CD34+ progenitor cells

2001

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“…[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.…”

Section: Introductionmentioning

confidence: 99%

“…23,44,48,49 In vitro manipulation of WT1 expression has been shown to affect the growth potential and differentiation of hematopoietic cells, leukemia cells, and cell lines. [19][20][21][22][23][24][25][26][27][28] Despite the use of WT1 as a therapeutic target and an indicator of prognosis in leukemia, the role of the WT1 gene in hematopoiesis is not clearly understood. We have used the targeted deletion of WT1 gene function in the mouse to directly investigate the role of WT1 in normal hematopoiesis.…”

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confidence: 99%

Role of the WT1 tumor suppressor in murine hematopoiesis

Alberta

Springett

Rayburn

et al. 2003

Blood

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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...

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“…9,10 The role of WT1 in hematopoiesis has been investigated in several leukemic cell lines with results that appear to be cell line specific. [11][12][13][14][15][16] Experiments using a nontransformed cell line, such as 32D cl3, may more accurately reflect the function of WT1 in normal hematopoiesis. 32D cl3 cells are interleukin-3 (IL-3) dependent, differentiate in response to granulocyte-colony stimulating factor (G-CSF), 17,18 and do not express endogenous WT1.…”

Section: Introductionmentioning

confidence: 99%

An isoform of the Wilms' tumor suppressor gene potentiates granulocytic differentiation

et al. 2003

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Downregulation of Wilms’ tumor gene (WT1) is not a prerequisite for erythroid or megakaryocytic differentiation of the leukemic cell line K562

Cited by 13 publications

References 27 publications

Forced expression of the Wilms tumor 1 (WT1) gene inhibits proliferation of human hematopoietic CD34+ progenitor cells

Forced expression of the Wilms tumor 1 (WT1) gene inhibits proliferation of human hematopoietic CD34+ progenitor cells

Role of the WT1 tumor suppressor in murine hematopoiesis

An isoform of the Wilms' tumor suppressor gene potentiates granulocytic differentiation

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