Yolk sac erythromyeloid progenitors expressing gain of function PTPN11 have functional features of JMML but are not sufficient to cause disease in mice

Tarnawsky, Stefan P.; Yoshimoto, Momoko; Deng, Lisa; Chan, Rebecca J.; Yoder, Mervin C.

doi:10.1002/dvdy.24598

Cited by 7 publications

(10 citation statements)

References 79 publications

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“…First, post-transplant hematopoiesis is markedly different from unperturbed hematopoiesis. Transplanted progenitors have altered lifespans, biased differentiation potentials, and frequently give rise to different disease manifestations when compared with progenitors in non-transplanted hosts [ 15 – 17 ]. Second, whereas somatic JMML mutations are restricted to hematopoietic cells, the majority of Cre stains used in the study of JMML have promiscuous tissue activity.…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic-restricted Ptpn11E76K reveals indolent MPN progression in mice

Tarnawsky

Wang

et al. 2018

Oncotarget

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Juvenile Myelomonocytic Leukemia (JMML) is a pediatric myeloproliferative neoplasm (MPN) that has a poor prognosis. Somatic mutations in Ptpn11 are the most frequent cause of JMML and they commonly occur in utero. Animal models of mutant Ptpn11 have probed the signaling pathways that contribute to JMML. However, existing models may inappropriately exacerbate MPN features by relying on non-hematopoietic-restricted Cre-loxP strains or transplantations into irradiated recipients. In this study we generate hematopoietic-restricted models of Ptpn11E76K-mediated disease using Csf1r-MCM and Flt3Cre. We show that these animals have indolent MPN progression despite robust GM-CSF hypersensitivity and Ras-Erk hyperactivation. Rather, the dominant pathology is pronounced thrombocytopenia with expanded extramedullary hematopoiesis. Furthermore, we demonstrate that the timing of tamoxifen administration in Csf1r-MCM mice can specifically induce recombinase activity in either fetal or adult hematopoietic progenitors. We take advantage of this technique to show more rapid monocytosis following Ptpn11E76K expression in fetal progenitors compared with adult progenitors. Finally, we demonstrate that Ptpn11E76K results in the progressive reduction of T cells, most notably of CD4+ and naïve T cells. This corresponds to an increased frequency of T cell progenitors in the thymus and may help explain the occasional emergence of T-cell leukemias in JMML patients. Overall, our study is the first to describe the consequences of hematopoietic-restricted Ptpn11E76K expression in the absence of irradiation. Our techniques can be readily adapted by other researchers studying somatically-acquired blood disorders.

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Section: Introductionmentioning

confidence: 99%

Hematopoietic-restricted Ptpn11E76K reveals indolent MPN progression in mice

Tarnawsky

Wang

et al. 2018

Oncotarget

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“…For this purpose, the ptpn11 gain-of-function JMML-initiating mutation had been introduced into EMPs. Although mice demonstrated features of JMML and mutant EMPs engrafted spleens of neonatal recipients, the disease was not transplantable ( Tarnawsky et al, 2017 ).…”

Section: An Hsc-independent Origin Of Pediatric Leukemia?mentioning

confidence: 99%

Prenatal Origin of Pediatric Leukemia: Lessons From Hematopoietic Development

Cazzola

Cazzaniga

Biondi

et al. 2021

Front. Cell Dev. Biol.

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Several lines of evidence suggest that childhood leukemia, the most common cancer in young age, originates during in utero development. However, our knowledge of the cellular origin of this large and heterogeneous group of malignancies is still incomplete. The identification and characterization of their cell of origin is of crucial importance in order to define the processes that initiate and sustain disease progression, to refine faithful animal models and to identify novel therapeutic approaches. During embryogenesis, hematopoiesis takes place at different anatomical sites in sequential waves, and occurs in both a hematopoietic stem cell (HSC)-dependent and a HSC-independent fashion. Despite the recently described relevance and complexity of HSC-independent hematopoiesis, few studies have so far investigated its potential involvement in leukemogenesis. Here, we review the current knowledge on prenatal origin of leukemias in the context of recent insights in developmental hematopoiesis.

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“…These evidences suggested a fetal origin for JMML, confirmed by the retrospective analysis of JMML patient samples collected at birth ( Kratz et al, 2005 ; Matsuda et al, 2010 ; Stieglitz et al, 2015 ). However, yolk sac EMPs expressing gain of function PTPN11 mutations recapitulate part of the characteristics of JMML, but they are not able to cause disease in mice ( Tarnawsky et al, 2017 ). Recently, gene expression profiling of JMML samples identified a subgroup characterized by high LIN28B expression and higher HbF levels ( Helsmoortel et al, 2016b ).…”

Section: Inappropriate Timing Of γ-Globin Expression In “Fetal-type” mentioning

confidence: 99%

Physiological and Aberrant γ-Globin Transcription During Development

Barbarani

Labedz

Stucchi

et al. 2021

Front. Cell Dev. Biol.

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The expression of the fetal Gγ- and Aγ-globin genes in normal development is confined to the fetal period, where two γ-globin chains assemble with two α-globin chains to form α2γ2 tetramers (HbF). HbF sustains oxygen delivery to tissues until birth, when β-globin replaces γ-globin, leading to the formation of α2β2 tetramers (HbA). However, in different benign and pathological conditions, HbF is expressed in adult cells, as it happens in the hereditary persistence of fetal hemoglobin, in anemias and in some leukemias. The molecular basis of γ-globin differential expression in the fetus and of its inappropriate activation in adult cells is largely unknown, although in recent years, a few transcription factors involved in this process have been identified. The recent discovery that fetal cells can persist to adulthood and contribute to disease raises the possibility that postnatal γ-globin expression could, in some cases, represent the signature of the fetal cellular origin.

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Yolk sac erythromyeloid progenitors expressing gain of function PTPN11 have functional features of JMML but are not sufficient to cause disease in mice

Cited by 7 publications

References 79 publications

Hematopoietic-restricted Ptpn11E76K reveals indolent MPN progression in mice

Hematopoietic-restricted Ptpn11E76K reveals indolent MPN progression in mice

Prenatal Origin of Pediatric Leukemia: Lessons From Hematopoietic Development

Physiological and Aberrant γ-Globin Transcription During Development

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