Molecular mechanisms of thrombopoietin signaling

Kaushansky, Kenneth

doi:10.1111/j.1538-7836.2009.03419.x

Cited by 48 publications

(42 citation statements)

References 35 publications

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“…In leukemic blasts, the expression of MPL receptor on the cell membrane may be originating from other transcription factors or by other mechanisms during the biosynthesis, trafficking, recycling, and degradation of MPL. 40 As a class I mutation, THPO/MPL activated signaling may be functionally redundant with other RTK mutations, and the t(8;21) AML cases analyzed with MPL expression analyzed showed a correlation to the absence of other known class I mutations. Activation of MPL elicits proliferative and prosurvival functions in HSCs and megakaryocytes through activation of PI3K/AKT/ mTOR, MEK/ERK, and JAK/STAT cascades.…”

Section: Discussionmentioning

confidence: 96%

“…Activation of MPL elicits proliferative and prosurvival functions in HSCs and megakaryocytes through activation of PI3K/AKT/ mTOR, MEK/ERK, and JAK/STAT cascades. 40 The MPL receptor lacks intrinsic tyrosine kinase activity, unlike other members of the cytokine receptor superfamily. Thpo/Mpl-mediated phosphorylation of Jak2 is critical for Mpl phosphorylation and activation.…”

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confidence: 99%

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Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling

Pulikkan

Madera

et al. 2012

Blood

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IntroductionAcute myeloid leukemia (AML) results from mutations in genes associated with proliferation, differentiation, and survival of hematopoietic progenitor cells, including genes encoding transcription factors and cytokine receptors that are essential for normal hematopoietic function. The simplistic but valid model of a multistep pathogenesis of AML proposes that class I mutations provide proliferative and survival advantage, and cooperate with class II mutations that block differentiation. 1 The chromosome translocation t(8;21) is a class II mutation found in 10% of AML samples, which breaks and joins the core binding factor (CBF) RUNX1 and ETO genes to create the leukemia fusion gene RUNX1-ETO (also called AML1-ETO; henceforth R1E). 2 R1E inhibits differentiation of hematopoietic progenitors and increases survival in vitro. 3,4 R1E expression is not sufficient for leukemic transformation in animal models, 5 but it induces AML in cooperation with mutations in genes encoding components of cytokine signaling pathways, such as the receptor tyrosine kinases (RTK) c-KIT and FLT3, and their downstream GTPases NRAS and KRAS. [6][7][8][9][10] The myeloproliferative leukemia virus oncogene, MPL (also called c-MPL or CD110), is a homodimeric receptor activated by the cytokine thrombopoietin (THPO) that regulates proliferation in hematopoietic stem cells (HSCs) and megakaryocytes. 11 Expression of Mpl is found in 70% of HSCs and is markedly reduced on HSC differentiation. 12,13 The number and function of HSCs are markedly reduced in Mpl-null and Thpo-null mice. 14-16 Selfrenewal capacity of long-term HSCs is reduced 10-to 20-fold in Thpo-null recipients, an effect that can be rescued with the addition of recombinant Thpo. 17 THPO/MPL signaling regulates the proliferation and maintenance of HSCs and early progenitors via activation of JAK/STAT, ERK/MEK, and PI3K/AKT pathways. 11 Mutations identified in human disease also highlight the importance of MPL signaling in homeostasis of the hematopoetic compartment. Nonsense mutations in the MPL and THPO genes cause congenital amegakaryocytic thrombocytopenia, with severe thrombocytopenia and aplastic anemia. 18 Somatic activating mutations in MPL cause constitutive JAK2 activation and are associated with myeloproliferative neoplasms, including myelofibrosis with myeloid metaplasia and essential thrombocythemia. 19,20 Activating mutations in the MPL gene have been detected in a small fraction of megakaryoblastic AML. 21 However, the oncogenic role of wildtype MPL in leukemia is not well understood.In this study, we used human AML cells and mouse transplantation models to study the role of MPL in R1E leukemia development. These studies show that MPL expression confers an oncogenic signal that cooperates with R1E in initiating and maintaining leukemia. Expression of wild-type MPL expression in t(8;21)-positive cells provides a survival and proliferative advantage via activating the THPO/MPL/PI3K/AKT axis. Methods Quantitative RT-PCR analysesRNA from mouse BM and leukemic cel...

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling

Pulikkan

Madera

et al. 2012

Blood

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“…This THPO-MPL interaction initiates several intracellular signaling cascades, including the JAK/STAT, RAS/MAPK, and PI3K/AKT pathways ( Figure 1B). 13,20 In mice, knockout studies for either Thpo or Mpl show a significant decrease in the numbers of myeloid, erythroid, megakaryocytic, and burst colony-forming units, but only peripheral blood thrombocytopenia. [21][22][23][24] Heterozygous gain-of-function mutations in THPO cause thrombocythemia, a chronic myeloproliferative syndrome that results in elevated numbers of circulating platelets, thrombotic or hemorrhagic episodes, and occasional leukemic transformation.…”

Section: Introductionmentioning

confidence: 99%

Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia

Dasouki

Rafi

Olm-Shipman

et al. 2013

Blood

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Key Points• Recessive mutations in the thrombopoietin gene are a novel cause of aplastic anemia.• Such patients may benefit from treatment with eltrombopag or romiplostim.We recently identified 2 siblings afflicted with idiopathic, autosomal recessive aplastic anemia. Whole-exome sequencing identified a novel homozygous missense mutation in thrombopoietin (THPO, c.112C>T) in both affected siblings. This mutation encodes an arginine to cysteine substitution at residue 38 or residue 17 excluding the 21-amino acid signal peptide of THPO receptor binding domain (RBD). THPO has 4 conserved cysteines in its RBD that form 2 disulfide bonds. Our in silico modeling predicts that introduction of a fifth cysteine may disrupt normal disulfide bonding to cause poor receptor binding. In functional assays, the mutant-THPO-containing media shows two-to threefold reduced ability to sustain UT7-TPO cells, which require THPO for proliferation. Both parents and a sibling with heterozygous R17C change have reduced platelet counts, whereas a sibling with wild-type sequence has normal platelet count. Thus, the R17C partial loss-of-function allele results in aplastic anemia in the homozygous state and mild thrombocytopenia in the heterozygous state in our family. Together with the recent identification of THPO receptor (MPL) mutations and the effects of THPO agonists in aplastic anemia, our results have clinical implications in the diagnosis and treatment of patients with aplastic anemia and highlight a role for the THPO-MPL pathway in hematopoiesis in vivo.

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“…15,16 TPO interacts with its cognate receptor, C-MPL, which activates JAK/STAT signaling. [17][18][19] TPO is a 4-helix bundle class I cytokine, and its amino-terminal domain has significant homology to EPO. 20 In mammals, TPO's C-terminal portion encodes a highly glycosylated regulatory domain.…”

Section: Introductionmentioning

confidence: 99%