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TpoR Agonist signaling in AML primary cells

ABSTRACT: Biologic characterization of SB-559457 (SB), a non-peptidyl hydrazone class of thrombopoietin receptor (Mpl) agonist, revealed toxicity towards human leukemia cells. Anti-proliferative effects followed by significant, non-apoptotic, cell death within 72 hours occurred in 24/26 AML, 0/6 ALL, and 3/6 CML patient samples exposed to SB, but not recombinant human thrombopoietin (rhTpo), in liquid suspension culture. Further investigation revealed increased phosphorylation of p70S6/S6 kinases in SB, but not in rhTpo, treated cells. Expression profiling of cells exposed to SB vs rhTpo revealed statistically significant, ~2-fold changes in GAPDH and REDD1 gene expression, confirmed by QRT-PCR. These genes, induced in energy or hypoxia stressed cells, have been implicated in cell death pathways, and may provide important clues to the mechanism of SB induced, leukemic cell death. These results suggest that nonpeptidyl, hydrazone class Mpl agonists may be clinically useful anti-leukemic agents by virtue of their combined thrombopoietic and anti-leukemic effects.

ORGANISM(S): Homo sapiens

PROVIDER: GSE18673 | GEO | 2009/10/22

SECONDARY ACCESSION(S): PRJNA121545

REPOSITORIES: GEO

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Transcription profiling of human patients with acute myeloid leukemia (AML) were stimulated stimulated with MPL receptor agonist (SB559457) or recombinant human Tpo (rhTpo) for 6 hours

Project description:Biologic characterization of SB-559457 (SB), a non-peptidyl hydrazone class of thrombopoietin receptor (Mpl) agonist, revealed toxicity towards human leukemia cells. Anti-proliferative effects followed by significant, non-apoptotic, cell death within 72 hours occurred in 24/26 AML, 0/6 ALL, and 3/6 CML patient samples exposed to SB, but not recombinant human thrombopoietin (rhTpo), in liquid suspension culture. Further investigation revealed increased phosphorylation of p70S6/S6 kinases in SB, but not in rhTpo, treated cells. Expression profiling of cells exposed to SB vs rhTpo revealed statistically significant, ~2-fold changes in GAPDH and REDD1 gene expression, confirmed by QRT-PCR. These genes, induced in energy or hypoxia stressed cells, have been implicated in cell death pathways, and may provide important clues to the mechanism of SB induced, leukemic cell death. These results suggest that nonpeptidyl, hydrazone class Mpl agonists may be clinically useful anti-leukemic agents by virtue of their combined thrombopoietic and anti-leukemic effects. Experiment Overall Design: Primary cells collected from 5 patients with acute myeloid leukemia (AML) were stimulated stimulated with MPL receptor agonist (SB559457) or recombinant human Tpo (rhTpo) for 6 hours. Next, RNA was isolated from these cells. RNA was used for gene profile analyis to compare genes regulated in AML cells by SB559457 verus rhTpo. For each sample half of the cells were stimulated with Mpl agonist and half with rhTpo.

2009-11-10 | E-GEOD-18673 | biostudies-arrayexpress

Role of MPL expression in determining heterogeneity of leukemia-initiating capacity of chronic myelogenous leukemia stem cells

Project description:Using a CML mouse model, we identified differences in gene expression between leukemic compared with non-leukemic LTHSC, including increased expression of the thrombopoietin (THPO) receptor MPL. LTHSC expressing high levels of MPL showed enhanced JAK/STAT signaling and proliferation in response to THPO in vitro, and increased leukemogenic capacity in vivo compared to LTHSC with low MPL expression. Although both G0 and S-phase subpopulations were increased in MPL expressing LTHSC, LSC capacity was restricted to quiescent cells. Inhibition of MPL expression in CML LTHSC resulted in reduced THPO-induced JAK/STAT signaling and leukemogenic potential. Similar observations were made with LTHSC from CML patients. MPL expressing LTHSC demonstrated reduced sensitivity to BCR-ABL TKI treatment but demonstrated increased sensitivity to JAK inhibitors. Our studies identify MPL expression levels as a key determinant of heterogeneous leukemia-initiating capacity and drug sensitivity of CML LTHSC, and suggest that MPL-expressing CML stem cells are critical targets for therapy. To evaluate heterogeneity in LSC potential, donor LTHSC from SCL-tTA/BCR-ABL mice (200 cells/mouse) were transplanted into a cohort of congenic FVBN mice. Recipient mice were followed for engraftment of donor CML cells and development of CML. LTHSCs were isolated from leukemic and non-leukemic recipient mice and global gene expression was analyzed using RNA-Seq.

2016-06-01 | E-GEOD-76123 | biostudies-arrayexpress

Role of MPL expression in determining heterogeneity of leukemia-initiating capacity of chronic myelogenous leukemia stem cells

2016-06-01 | GSE76123 | GEO

Expanding Hematopoietic Stem Cell pool through Fine tuning of Tpo receptor with diabodies.

Project description:Class I cytokine receptors such as Thrombopoietin receptor (MPL) are dimers, but it is unclear whether remodeling receptor dimer topology is a viable strategy to "tune" signaling output. We utilized diabodies (DA) as surrogate ligands in a prototypical dimeric receptor-ligand system, the cytokine Thrombopoietin (TPO) and its receptor (TpoR), to dimerize TpoR ectodomains in non-native architectures. Diabody-induced signaling amplitudes varied from full to minimal agonism. Here we describe a single-cell transcriptome analysis of 659 human Hematopoietic Stem Cells cultured with different DA. We find several difference between differentiation and activation of signaling pathways compared to TPO.

2021-02-01 | GSE115235 | GEO

RNA-SEQ Quantitative Analysis of WT and Mpl-del-overexpressing AMKL cell Transcriptomes

Project description:In the previous studies, we reported that Mpl alternative splicing form Mpl-del overexpressed in acute megakaryoblasttic leukemia (AMKL) patients and mediated thrombopoietin signaling to promote AMKL cells malignant proliferation and chemotherapy resisitance. To investigate the detailed mechanism of Mpl-del mediated AMKL cells proliferation and survival, the AMKL cell Dami stably expressing GFP or Mpl-del-GFP were established by transduction with GFP or Mpl-del-GFP lentiviruses and treated with 20ng/ml TPO for RNA-SEQ analysis to examine the expression of proliferation and survival-related genes. Our results indicated that the levels of the "leading edge" genes that account for survival and prolieration were significantly higher in Mpl--del overexpressed AMKL cells.

2019-04-04 | GSE127762 | GEO

RNA-SEQ Quantitative Analysis of the regulation of c-Mpl-del on survival related gene transcriptome in AMKL cells

Project description:In the previous studies, we reported that c-Mpl alternative splicing form c-Mpl-del overexpressed in acute megakaryoblasttic leukemia (AMKL) patients and mediated thrombopoietin signaling to promote AMKL cells malignant proliferation and chemotherapy resisitance. To investigate the detailed mechanism of c-Mpl-del mediated AMKL cells survival and chemotherapy resisitance, the AMKL cell Dami stably expressing GFP, c-Mpl-del-GFP or c-Mpl-p-GFP were established by transduction with GFP, c-Mpl-del-GFP or c-Mpl-p-GFP lentiviruses and treated with or without Ara-c (10μM) in the presence of 20ng/mL TPO for RNA-SEQ analysis to exame the expression of survival-related genes. Our results indicate that the levels of the "leading edge" genes that account for survival and prolieration are significantly higher in c-Mpl-del overexpressed AMKL cells. Meanwhile, the expression of c-Mpl-del promotes the tolerance of AMKL cells to Ara-c.

2020-02-27 | GSE145949 | GEO

Deciphering the Differential Impact of Thrombopoietin/MPL Signaling on Hematopoietic Stem Cell Function in Bone Marrow and Spleen

Project description:Thrombopoietin (TPO) and its receptor MPL play crucial roles in hematopoietic stem cell (HSC) function and platelet production. However, the precise effects of TPO/MPL signaling on HSC regulation in different hematopoietic niches remain unclear. Here, we investigated the effects of TPO/MPL ablation on marrow and splenic hematopoiesis in TPO-/- and MPL-/- mice during aging. Despite severe thrombocytopenia, TPO-/- and MPL-/- mice did not develop marrow failure during a 2-year follow-up. Marrow and splenic HSCs exhibited different responses to TPO/MPL ablation and exogenous TPO treatment. Splenic niche cells compensated for marrow HSC loss in TPO-/- and MPL-/- mice by upregulating CXCL12 levels. These findings provide new insights into the complex regulation of HSCs by TPO/MPL and reveal a previously unknown link between TPO and CXCL12, two key growth factors for HSC maintenance. Understanding the distinct regulatory mechanisms between marrow and spleen hematopoiesis will help develop novel therapeutic approaches for hematopoietic disorders.

2023-12-16 | GSE249912 | GEO

Oncogenic Calreticulin Induces Immune Escape by Stimulating TGF-β Expression and Regulatory T Cell Expansion in the Bone Marrow Microenvironment - microarray

Project description:To understand transcriptional aberrations induced by oncogenic Calreticulin (Calr) in myeloproliferative neoplasms we used a cell line – 32D, generated from the murine myeloid precursor cells, to overexpress human thrombopoietin receptor (MPL) together with human Calr. Cells expressing oncogenic Calr show increased JAK/STAT signaling independent of extrinsic stimuli like IL3.

2024-05-30 | GSE241162 | GEO

Gene expression changes induced by expression of dMPL in murine bone haematopoietic progenitor cells

Project description:Thrombopoietin (Thpo) signals via its receptor Mpl and regulates megakaryopoiesis, hematopoietic stem cell (HSC) maintenance and post-transplant expansion. Mpl expression is tightly controlled and deregulation of Thpo/Mpl-signaling is linked to hematological disorders. Here, we constructed an intracellular-truncated, signaling deficient Mpl protein which is presented on the cell surface (dnMpl). The transplantation of bone marrow cells retrovirally transduced to express dnMpl into wildtype mice induced thrombocytopenia, and a progressive loss of HSC. Functional analysis of the truncated Mpl in vitro and in vivo demonstrated no internalization after Thpo binding and the inhibition of Thpo/Mpl-signaling in wildtype cells due to dominant-negative (dn) effects by receptor competition with wildtype Mpl for Thpo binding. Gene expression analysis was performerd of Lin-Sca1+cKit+ (LSK) cells isolated from mice transplanted with dnMpl transduced BM cells. The gene expression profile supported the exhaustion of HSC due to increased cell cycle progression and identified new and known downstream effectors of Thpo/Mpl-signaling in HSC (namely TIE2, ESAM1 and EPCR detected on the HSC-enriched LSK cell population). In summary, we established a novel way of Thpo/Mpl inhibition in the adult mouse and performed in depth analysis of the phenotype including gene expression profiling.

2015-07-31 | GSE69209 | GEO

Differential in vivo roles of Mpl cytoplasmic tyrosine residues in murine hematopoiesis and myeloproliferative disease

Project description:Thrombopoietin (Tpo), which binds to its specific receptor, the Mpl protein, is the major cytokine regulator of megakaryopoiesis and circulating platelet number. Produced primarily in the liver, Tpo binds to Mpl on the surface of target cells triggering activation of Janus kinase 2 (Jak2) and phosphorylation of the receptor, as well as activation of several intracellular signalling cascades that mediate cellular responses. Three tyrosine (Y) residues in the C-terminal region of the Mpl intracellular domain have been implicated as sites of phosphorylation required for the activation and regulation of major Tpo-stimulated signalling pathways: Mpl-Y565, Mpl-Y599 and Mpl-Y604. Here, we have introduced mutations in the mouse germline to define the roles of Mpl receptor intracellular domains and tyrosine residues in steady-state and pathophysiological actions of Tpo/Mpl signalling. We report a consistent physiological requirement for Mpl-Y599, absence of which resulted in thrombocytopenia, deficient megakaryopoiesis, low hematopoietic stem cell (HSC) number and function, and attenuated responses to myelosuppression caused by administration of 5-fluorouracil (5-FU). We further show that in models of myeloproliferative neoplasms (MPN) driven by mutations in Jak2 or hCalr, where Mpl is required for pathogenesis, thrombocytosis was dependent on intact Mpl-Y599. In contrast, Mpl-Y565 was required for negative regulation of Tpo responses; mutation of this residue resulted in excess megakaryopoiesis at steady-state and in response to 5-FU, and exacerbated mutant Jak2 and hCalr-driven thrombocytosis.

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