Critical Role of Jak2 in the Maintenance and Function of Adult Hematopoietic Stem Cells

Akada, Hajime; Akada, Saeko; Hutchison, Robert; Sakamoto, Kazuhiro; Wagner, Kay Uwe; Mohi, Golam

doi:10.1002/stem.1711

Cited by 75 publications

(57 citation statements)

References 44 publications

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“…Recently, an essential role for Jak2 in adult HSC maintenance and self-renewal has been demonstrated. 43,44 We now show that Jak2 is also crucially required for the function of the first HSCs that emerge in the AGM. Their generation and survival appear normal; however, they are compromised in their repopulation and self-renewal ability.…”

Section: Discussionmentioning

confidence: 67%

Analysis of Jak2 signaling reveals resistance of mouse embryonic hematopoietic stem cells to myeloproliferative disease mutation

Mascarenhas

Bacon

Kapeni

et al. 2016

Blood

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Key Points• Emerging HSCs require Jak2 and Pi3k signaling for proliferation and survival.• Embryonic HSCs are unaffected by the JAK2V617F mutation.The regulation of hematopoietic stem cell (HSC) emergence during development provides important information about the basic mechanisms of blood stem cell generation, expansion, and migration. We set out to investigate the role that cytokine signaling pathways play in these early processes and show here that the 2 cytokines interleukin 3 and thrombopoietin have the ability to expand hematopoietic stem and progenitor numbers by regulating their survival and proliferation. For this, they differentially use the Janus kinase (Jak2) and phosphatidylinositol 3-kinase (Pi3k) signaling pathways, with Jak2 mainly relaying the proproliferation signaling, whereas Pi3k mediates the survival signal. Furthermore, using Jak2-deficient embryos, we demonstrate that Jak2 is crucially required for the function of the first HSCs, whereas progenitors are less dependent on Jak2. The JAK2V617F mutation, which renders JAK2 constitutively active and has been linked to myeloproliferative neoplasms, was recently shown to compromise adult HSC function, negatively affecting their repopulation and self-renewal ability, partly through the accumulation of JAK2V617F-induced DNA damage. We report here that nascent HSCs are resistant to the JAK2V617F mutation and show no decrease in repopulation or selfrenewal and no increase in DNA damage, even in the presence of 2 mutant copies. More importantly, this unique property of embryonic HSCs is stably maintained through ‡1 round of successive transplantations. In summary, our dissection of cytokine signaling in embryonic HSCs has uncovered unique properties of these cells that are of clinical importance.

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Section: Discussionmentioning

confidence: 67%

Analysis of Jak2 signaling reveals resistance of mouse embryonic hematopoietic stem cells to myeloproliferative disease mutation

Mascarenhas

Bacon

Kapeni

et al. 2016

Blood

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“…16 JAK2 is a member of the Janus kinase family of nonreceptor protein tyrosine kinases and has an important role in the cellular development and homeostasis. 17 Though, overactivity of the JAK2, chiefly under the effect of JAK2 (V617F) mutation, is well-known in myeloproliferative neoplasms, 16,18,19 its effect in melanocytic disorders has not been elucidated yet.…”

Section: Discussionmentioning

confidence: 99%

Lentiginoses in polycythemia vera patient: Is there a role forJAK2 (V617F)mutation?

et al. 2015

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ABSTRACT. Lentiginoses is a clinical feature in which lentigines are remarkably present in large numbers or when they occur in a distinctive distribution on apparently normal skin. This entity may be congenital or acquired and may cover a wide spectrum of diseases ranging from an isolated benign pigmentary disorder to numerous syndromes associated with molecular abnormalities.We present a 59-year-old female patient with multiple lentigines which first emerged 3 y ago concurrently with policytemia vera. The patient had found to be positive for Janus Kinase-2 (JAK-2) mutation. Over activation of the pathway due to JAK-2 V617F mutation is a well-known condition in myeloproliferative diseases but has not been reported in melanocytic disorders. Moreover, several signaling pathways have previously been defined with lentiginosis except JAK-STAT pathway. We want to draw attention to the potential effect of JAK-2 mutation in lentigogenesis with this case report.

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“…As outlined in Figure 1, JAK2 plays a role in the function and maintenance of hematopoietic stem cells 28 by participating directly in signal transduction of thrombopoietin (TPO) 29 and by contributing to signaling downstream of the stem cell factor.…”

Section: Role Of Jak Kinases In Hematopoiesismentioning

confidence: 99%

JAK kinase targeting in hematologic malignancies: a sinuous pathway from identification of genetic alterations towards clinical indications

2015

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In 2005, several groups reported a unique, acquired, somatic activating mutation of JAK2 (V617F) in 95% of patients with polycythemia vera (PV) and in about half of those with essential thombocythemia (ET) or primary myelofibrosis (MF). [6][7][8][9] The discovery of JAK2 V617F led to screening for JAK mutations in other hematologic neoplasms. Thanks to improvements of sequencing techniques and the conduction of massive sequencing projects, the catalogue of genetic alterations in hematologic malignancies is constantly being updated as ever more new mutational targets are discovered. This review provides an overview of the different molecular mechanisms underlying constitutive activation of the JAK-STAT pathway and their respective frequencies among hematologic neoplasms. The use of JAK inhibitors in the clinic and in ongoing trials, resistance phenomena as well as future challenges are discussed. The review begins by documenting insights into the structural organization of JAK kinases, their mode of activation as well as the role of the different family members in hematopoiesis. Janus kinasesJAK1, JAK2 and TYK2 tyrosine kinases are ubiquitously expressed and non-covalently bound to a distinct, mostly non-overlapping repertory of receptor chains. By contrast, JAK3 expression is restricted to the hematopoietic lineage and it associates exclusively with the common gammachain (γc). Based on their primary sequences, JAK kinases were initially divided into seven highly conserved JAK homology regions (JH1-7, starting from the C-terminal end) but were subsequently organized into four functional domains. 10The N-terminal moiety of JAK kinases constitutes the receptor-binding module with a FERM (band 4.1, ezrin, radixin, moesin) domain (JH4-7) and an atypical SH2 domain (JH3).11 It has been experimentally established that both domains do not exist as individual functional entities but structurally cooperate for non-covalent anchoring to two membrane-proximal regions of defined receptors. 12,13 This was corroborated by a recent crystal structure study showing that the N-terminal part of TYK2 forms a con-JAK kinase targeting in hematologic malignancies haematologica | 2015; 100 (10) 1241 Figure 1. Hematopoiesis. Hematopoiesis originates from a hematopoietic stem cell, which can undergo either self-renewal or hierarchical differentiation into lineage-committed progenitors with decreasing potential that ultimately will give rise to all mature blood cells. Cytokines and their receptor-associated JAK necessary for the progenitors to pass through the different maturation steps are indicated. HSC: hematopoietic stem cell; CMP: common myeloid progenitor; CLP: common lymphoid progenitor; GM: granulocyte macrophage progenitor; BCP: B cell progenitor; TNK: T and natural killer cell progenitor; EP: erythroid progenitor; Mk: megakaryocyte; GP: granulocyte progenitor; MP: macrophage progenitor; TPO: thrombopoietin; SCF: stem cell factor; IL: interleukin; GM-CSF: granulocyte/monocyte colony-stimulating factor; G-CSF: granulocyte c...

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Critical Role of Jak2 in the Maintenance and Function of Adult Hematopoietic Stem Cells

Cited by 75 publications

References 44 publications

Analysis of Jak2 signaling reveals resistance of mouse embryonic hematopoietic stem cells to myeloproliferative disease mutation

Analysis of Jak2 signaling reveals resistance of mouse embryonic hematopoietic stem cells to myeloproliferative disease mutation

Lentiginoses in polycythemia vera patient: Is there a role forJAK2 (V617F)mutation?

JAK kinase targeting in hematologic malignancies: a sinuous pathway from identification of genetic alterations towards clinical indications

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