Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors

Mackarehtschian, Katrin; Hardin, Jeff; Moore, Katrd A.; Boast, Sharon; Goff, Stephen P.; Lemischka, Ihor R.

doi:10.1016/1074-7613(95)90167-1

Cited by 533 publications

(397 citation statements)

References 44 publications

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“…In each case, the hematopoietic system of animals with reduced or absent function for these tyrosine kinase receptors have decreased competitive efficiency of hematopoietic stem cells and negative effects on the differentiation of committed progenitors. 57,58 Deficiencies in stem cells and committed progenitors resembling the WT1 defect have also been described for mice lacking the thrombopoietin (TPO) receptor c-mpl and for mice lacking the growth factors interleukin-6 (IL-6), kit ligand and Lif, and the HOX cofactor Pbx1. 57,[59][60][61][62] Hematopoietic defects of WT1-deficient mice could be the consequence of the failure of regulation by WT1 of one or more hematopoietic signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…57,58 Deficiencies in stem cells and committed progenitors resembling the WT1 defect have also been described for mice lacking the thrombopoietin (TPO) receptor c-mpl and for mice lacking the growth factors interleukin-6 (IL-6), kit ligand and Lif, and the HOX cofactor Pbx1. 57,[59][60][61][62] Hematopoietic defects of WT1-deficient mice could be the consequence of the failure of regulation by WT1 of one or more hematopoietic signaling pathways. If receptor expression levels are reduced by the absence of WT1, a hematopoietic phenotype resembling the WT1-negative hematopoietic cell would be expected.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Role of the WT1 tumor suppressor in murine hematopoiesis

Alberta

Springett

Rayburn

et al. 2003

Blood

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“…For instance, factors in the IL-6 family maintain the pluripotentiality of mouse embryonic stem (ES) cells through activation of the STAT3 pathway [22][23][24][25][26][27]. In addition, growth of human primordial germ cells requires LIF, SCF, and bFGF [28], whereas SCF, FLT3L, TPO, and IL-6 synergize with each other to promote expansion of hematopoietic progenitors [29][30][31][32][33][34][35][36][37]. In this report, we demonstrate that hESCs can be maintained in bFGF or bFGF in combination with other growth factors in a serum replacement nonconditioned medium (SR medium).…”

Section: Introductionmentioning

confidence: 99%

Basic Fibroblast Growth Factor Supports Undifferentiated Human Embryonic Stem Cell Growth Without Conditioned Medium

et al. 2005

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Previous studies have shown that prolonged propagation of undifferentiated human embryonic stem cells (hESCs) requires conditioned medium from mouse embryonic feeders (MEF-CM) as well as matrix components. Because hESCs express growth factor receptors, including those for basic fibroblast growth factor (bFGF), stem cell factor (SCF), and fetal liver tyrosine kinase-3 ligand (Flt3L), we evaluated these and other growth factors for their ability to maintain undifferentiated hESCs in the absence of conditioned medium. We found cultures maintained in bFGF alone or in combination with other factors showed characteristics similar to MEF-CM control cultures, including morphology, surface marker and transcription factor expression, telomerase activity, differentiation, and karyotypic stability. In contrast, cells in media containing Flt-3L, thrombopoietin, and SCF, individually or in combination, showed almost complete differentiation after 6 weeks in culture. These data demonstrate that hESCs can be maintained in nonconditioned medium using growth factors. 2005;23:315-323 Stem Cells

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“…21 FLT3 is integral to hematopoiesis through its regulation of proliferation, differentiation and apoptosis of hematopoietic progenitor cells. Knockout mice models have shown that lack of FLT3 ligand and FLT3 leads to reduced hematopoietic precursors, 22,23 demonstrating the importance of these proteins in hematopoietic expansion.…”

Section: Structure/function Of the Flt3 Receptor Flt3 Receptormentioning

confidence: 99%

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

2012

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Acute myeloid leukemia (AML) is a highly heterogenous disease with multiple signaling pathways contributing to its pathogenesis. A key driver of AML is the FMS-like tyrosine kinase receptor-3 (FLT3). Activating mutations in FLT3, primarily the FLT3-internal tandem duplication (FLT3-ITD), are associated with decreased progression-free and overall survival. Identification of the importance of FLT3-ITD and the FLT3 pathway in the prognosis of patients with AML has stimulated efforts to develop therapeutic inhibitors of FLT3. Although these inhibitors have shown promising antileukemic activity, they have had limited efficacy to date as single agents and may require use in combination with cytotoxic chemotherapies. Here, we review clinical and preclinical results for the clinically mature FLT3 inhibitors currently in development. We conclude that multitargeted FLT3 inhibitors may have more utility earlier in the course of disease, when in vitro evidence suggests that AML cells are less dependent on FLT3 signaling, perhaps because of upregulation of multiple other signaling pathways. More potent agents may have greater utility in relapsed and heavily pretreated patients, in whom high levels of circulating FLT3 ligand may necessitate use of an agent with a very favorable pharmacokinetic/ pharmacodynamic profile. Novel combination regimens are also discussed.

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Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors

Cited by 533 publications

References 44 publications

Role of the WT1 tumor suppressor in murine hematopoiesis

Role of the WT1 tumor suppressor in murine hematopoiesis

Basic Fibroblast Growth Factor Supports Undifferentiated Human Embryonic Stem Cell Growth Without Conditioned Medium

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

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