Impaired neutrophil maturation in truncated murine G-CSF receptor–transgenic mice

Mitsui, Tetsuo; Watanabe, Sumiko; Taniguchi, Yasushi; Hanada, Shigeo; Ebihara, Yasuhiro; Satô, Takeshi; Heike, Toshio; Mitsuyama, Masao; Nakahata, Tatsutoshi; Tsuji, Kohichiro

doi:10.1182/blood.v101.8.2990

Cited by 36 publications

(37 citation statements)

References 25 publications

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“…Truncation of the receptor also alters its downstream signaling, 25 which reduces the differentiative capacity of the receptor while continuing to allow for cellular proliferation. In a transgenic mouse model expressing the CSF3R truncation mutation, there is a reduction in steady-state neutrophil production, 28,29 but hyperproliferation occurs in response to treatment with GCSF. 29 In contrast to the CSF3R T618I mutation, the truncation mutations alone do not cause leukemia in mouse models, 29 but they can accelerate the development of disease in the presence of another genetic event driving leukemia.…”

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confidence: 99%

Genomics of chronic neutrophilic leukemia

Maxson¹,

Tyner

2017

Blood

101

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Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm with a high prevalence (>80%) of mutations in the colony-stimulating factor 3 receptor (CSF3R). These mutations activate the receptor, leading to the proliferation of neutrophils that are a hallmark of CNL. Recently, the World Health Organization guidelines have been updated to include CSF3R mutations as part of the diagnostic criteria for CNL. Because of the high prevalence of CSF3R mutations in CNL, it is tempting to think of this disease as being solely driven by this genetic lesion. However, recent additional genomic characterization demonstrates that CNL has much in common with other chronic myeloid malignancies at the genetic level, such as the clinically related diagnosis atypical chronic myeloid leukemia. These commonalities include mutations in SETBP1, spliceosome proteins (SRSF2, U2AF1), and epigenetic modifiers (TET2, ASXL1). Some of these same mutations also have been characterized as frequent events in clonal hematopoiesis of indeterminate potential, suggesting a more complex disease evolution than was previously understood and raising the possibility that an age-related clonal process of preleukemic cells could precede the development of CNL. The order of acquisition of CSF3R mutations relative to mutations in SETBP1, epigenetic modifiers, or the spliceosome has been determined only in isolated case reports; thus, further work is needed to understand the impact of mutation chronology on the clonal evolution and progression of CNL. Understanding the complete landscape and chronology of genomic events in CNL will help in the development of improved therapeutic strategies for this patient population.

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confidence: 99%

Genomics of chronic neutrophilic leukemia

Maxson¹,

Tyner

2017

Blood

101

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“…Expression of alternative cytokine receptor variants, which act as dominantnegative isoforms, can serve as a mechanism of modulating the responses to cytokines. [18][19][20] Mechanistically, dominant-negative receptor variants can form nonfunctional heterodimers with the full-length receptor or, when expressed as secreted "soluble" isoforms, compete with the receptor for ligand binding. 21 We have described a third mechanism, in which overexpression of the Mpl isoform Mpl-tr triggers protein degradation of the full-length receptor.…”

Section: Introductionmentioning

confidence: 99%

Pronounced thrombocytosis in transgenic mice expressing reduced levels of Mpl in platelets and terminally differentiated megakaryocytes

Tiedt

Coers

Ziegler

et al. 2009

Blood

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We generated mice expressing a fulllength Mpl transgene under the control of a 2-kb Mpl promoter in an Mpl Ϫ/Ϫ background, effectively obtaining mice that express full-length Mpl in the absence of other Mpl isoforms. These mice developed thrombocytosis with platelet levels approximately 5-fold higher than wildtype controls and markedly increased megakaryocyte numbers. The reintroduction of one wild-type Mpl allele restored normal platelet counts. We excluded the deletion of Mpl-tr, a dominant-negative isoform, as the underlying molecular cause for thrombocytosis. Instead, we found that transgene expression driven by the 2-kb Mpl promoter fragment was decreased during late megakaryocyte maturation, resulting in strongly diminished Mpl protein expression in platelets. Because platelets exert a negative feedback on thrombopoiesis by binding and consuming Tpo in the circulation through Mpl, we propose that the severe reduction of Mpl protein in platelets in Mpltransgenic Mpl ؊/؊ mice shifts the equilibrium of this feedback loop, resulting in markedly elevated levels of megakaryocytes and platelets at steady state. Although the mechanism causing decreased expression of Mpl protein in platelets from patients with myeloproliferative disorders differs from this transgenic model, our results suggest that lowering Mpl protein in platelets could contribute to raising the platelet count. IntroductionThrombopoietin (Tpo) and its receptor Mpl are the principal regulators of megakaryopoiesis. 1,2 Mice deficient in Tpo or Mpl continue to produce functional platelets, albeit at much lower levels, 3,4 suggesting that Mpl mainly controls quantitative aspects of thrombopoiesis. Tpo serum levels are controlled by the platelet mass through Mpl-mediated Tpo uptake and degradation. 5,6 Consequently, Mpl Ϫ/Ϫ mice show increased Tpo levels. 3 Although an important function of Mpl is to regulate platelet numbers, it is also expressed on hematopoietic stem cells (HSCs) and early progenitors. 7,8 Consistently, Mpl-deficient mice show markedly decreased numbers of hematopoietic progenitors, and competitive repopulation assays indicate that the numbers of murine HSCs is reduced by 7-to 8-fold. 7,8 In humans, loss-of-function mutations in Mpl lead to congenital amegakaryocytic thrombocytopenia, a disorder that frequently leads to bone marrow failure. [9][10][11] The reason for the more severe phenotype in humans remains unknown.Mutant versions of Mpl can lead to uncontrolled proliferation and survival signals as exemplified by the retroviral fusion oncogene v-Mpl, which can immortalize hematopoietic progenitors. 12 An autosomal-dominant point mutation in the transmembrane domain of Mpl (S505N) was identified as the cause of thrombocytosis in families with hereditary thrombocytosis. 13,14 Recently, point mutations in the cytoplasmic domain of Mpl (W515L, W515K) were identified in patients with primary myelofibrosis and essential thrombocythemia, and W515L was shown in mouse models to elicit myeloproliferative disease (MPD) with marked thromboc...

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“…Truncated receptors show normal affinity for G-CSF, 17 but transduce a strong hyperproliferative signal but a defective maturation signal when expressed in myeloid cells, 19 a result confirmed in mice expressing truncated G-CSF-Rs. 22,25,26 We and others have shown that this hyperproliferation is due, at least in part, to defective internalization, [27][28][29] as well as the loss of the receptor docking site for a string of negative regulators, including Src homology domain phosphatase-1, SH2 domain-containing 5 0 -phosphatase, cytokine-induced Src homology 2-containing protein and suppressor of cytokine signaling 3. [29][30][31] Collectively, this leads to a decreased 'offrate' 26,27,32 and extended activation of various signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

“…[17][18][19][20] This cohort of patients also exhibits a strong predisposition to acute myeloid leukemia (AML). 1 Although the role of G-CSF-R truncations in the etiology of SCN remains controversial, [21][22][23][24][25] there has been little argument about the contribution of such mutations to leukemogenesis. Truncated receptors show normal affinity for G-CSF, 17 but transduce a strong hyperproliferative signal but a defective maturation signal when expressed in myeloid cells, 19 a result confirmed in mice expressing truncated G-CSF-Rs.…”

Section: Introductionmentioning

confidence: 99%