Growth stimulatory effect of thrombopoietin on the blast cells of acute myelogenous leukaemia

Motoji, Toshiko; Takanashi, Minoko; Motomura, Sayuri; Wang, Yanhua; Shiozaki, Hiroko; Aoyama, Masako; Mizoguchi, Hideaki

doi:10.1046/j.1365-2141.1996.d01-1832.x

Cited by 25 publications

(16 citation statements)

References 8 publications

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“…29,30 A similar in vitro stimulating effect of G-CSF (and also of other cytokines) on in vitro proliferation of AML cells has been reported. 31 In spite of this, randomised clinical trials in patients with AML have not detected an effect of G-CSF administration on leukaemic cell growth.…”

Section: Figuresupporting

confidence: 54%

Recombinant human megakaryocyte growth and development factor (MGDF) increases the numbers of megakaryocyte progenitor cells to normal values in long-term bone marrow cultures of patients with AML in first remission

et al. 1998

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The megakaryopoietic potential in the bone marrow (BM) of patients in first remission after treatment for acute myelogenous leukaemia (AML) was investigated using long-term bone marrow cultures (LTC) stimulated with megakaryocyte growth and development factor (MGDF). The baseline number of megakaryocyte colony-forming cells (Meg-CFC) was very low. However, there was a 10 to 100-fold increase of Meg-CFC in cultures treated with 10 ng/ml MGDF with mean numbers within the normal range for the first 4 weeks of culture with a 24-fold increase in their cumulative numbers. Similarly, a 12-fold increase in the numbers of megakaryocytes (MKs) was found by CD61 immunostaining. These effects were lost at the dose of 100 ng/ml. In contrast, the cumulative mean numbers of Meg-CFC in the control cultures from normal bone marrow (NBM) were not significantly different from those in cultures treated with 10 or 100 ng/ml MGDF. These results demonstrate that MGDF stimulates megakaryocytopoiesis in patients with AML in first remission, restoring the Meg-CFC compartment to normal values, a result with potential clinical implications for their treatment with autologous transplantation.

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Section: Figuresupporting

confidence: 54%

Recombinant human megakaryocyte growth and development factor (MGDF) increases the numbers of megakaryocyte progenitor cells to normal values in long-term bone marrow cultures of patients with AML in first remission

et al. 1998

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“…Although we have no evidence for any biological significance of the patient groups used in this comparison other than TPO transcript level, we noted that the groupings appear to fall along the lines of samples with high or low percentage of blasts (see http://www.genome.wi.mit.edu/MPR). Interestingly, TPO can stimulate the proliferation of AML blasts (Motoji et al 1996;Luo et al 2000).…”

Section: Leukemia Studymentioning

confidence: 99%

An Efficient and Robust Statistical Modeling Approach to Discover Differentially Expressed Genes Using Genomic Expression Profiles

Thomas¹,

Olson²,

Tapscott³

et al. 2001

Genome Res.

286

192

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We have developed a statistical regression modeling approach to discover genes that are differentially expressed between two predefined sample groups in DNA microarray experiments. Our model is based on well-defined assumptions, uses rigorous and well-characterized statistical measures, and accounts for the heterogeneity and genomic complexity of the data. In contrast to cluster analysis, which attempts to define groups of genes and/or samples that share common overall expression profiles, our modeling approach uses known sample group membership to focus on expression profiles of individual genes in a sensitive and robust manner. Further, this approach can be used to test statistical hypotheses about gene expression. To demonstrate this methodology, we compared the expression profiles of 11 acute myeloid leukemia (AML) and 27 acute lymphoblastic leukemia (ALL) samples from a previous study ) and found 141 genes differentially expressed between AML and ALL with a 1% significance at the genomic level. Using this modeling approach to compare different sample groups within the AML samples, we identified a group of genes whose expression profiles correlated with that of thrombopoietin and found that genes whose expression associated with AML treatment outcome lie in recurrent chromosomal locations. Our results are compared with those obtained using t-tests or Wilcoxon rank sum statistics.

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“…There are differences between the amplitude and extent of signaling between TPO and eltrombopag [21]. Acute myeloid leukemia (AML) blasts have been shown to express TPO-R [22] and in some reports TPO has induced proliferation of these blasts [23], although investigations in leukemia cell lines show conflicting results [24,25]. A variety of human non-megakaryocytic leukemia and lymphoma cell lines show decreased, rather than increased, proliferation upon incubation with eltrombopag [26].…”

Section: Introductionmentioning

confidence: 99%

Low or undetectable TPO receptor expression in malignant tissue and cell lines derived from breast, lung, and ovarian tumors

et al. 2012

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BackgroundNumerous efficacious chemotherapy regimens may cause thrombocytopenia. Thrombopoietin receptor (TPO-R) agonists, such as eltrombopag, represent a novel approach for the treatment of chemotherapy-induced thrombocytopenia. The TPO-R MPL is expressed on megakaryocytes and megakaryocyte precursors, although little is known about its expression on other tissues.MethodsBreast, lung, and ovarian tumor samples were analyzed for MPL expression by microarray and/or quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and for TPO-R protein expression by immunohistochemistry (IHC). Cell line proliferation assays were used to analyze the in vitro effect of eltrombopag on breast, lung, and ovarian tumor cell proliferation. The lung carcinoma cell lines were also analyzed for TPO-R protein expression by Western blot.ResultsMPL mRNA was not detectable in 118 breast tumors and was detectable at only very low levels in 48% of 29 lung tumors studied by microarray analysis. By qRT-PCR, low but detectable levels of MPL mRNA were detectable in some normal (14-43%) and malignant (3-17%) breast, lung, and ovarian tissues. A comparison of MPL to EPOR, ERBB2, and IGF1R mRNA demonstrates that MPL mRNA levels were far lower than those of EPOR and ERBB2 mRNA in the same tissues. IHC analysis showed negligible TPO-R protein expression in tumor tissues, confirming mRNA analysis. Culture of breast, lung, and ovarian carcinoma cell lines showed no increase, and in fact, showed a decrease in proliferation following incubation with eltrombopag. Western blot analyses revealed no detectable TPO-R protein expression in the lung carcinoma cell lines.ConclusionsMultiple analyses of breast, lung, and ovarian tumor samples and/or cell lines show no evidence of MPL mRNA or TPO-R protein expression. Eltrombopag does not stimulate growth of breast, lung, or ovarian tumor cell lines at doses likely to exert their actions on megakaryocytes and megakaryocyte precursors.

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Growth stimulatory effect of thrombopoietin on the blast cells of acute myelogenous leukaemia

Cited by 25 publications

References 8 publications

Recombinant human megakaryocyte growth and development factor (MGDF) increases the numbers of megakaryocyte progenitor cells to normal values in long-term bone marrow cultures of patients with AML in first remission

Recombinant human megakaryocyte growth and development factor (MGDF) increases the numbers of megakaryocyte progenitor cells to normal values in long-term bone marrow cultures of patients with AML in first remission

An Efficient and Robust Statistical Modeling Approach to Discover Differentially Expressed Genes Using Genomic Expression Profiles

Low or undetectable TPO receptor expression in malignant tissue and cell lines derived from breast, lung, and ovarian tumors

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