Mechanisms of anemia in SHP-1 protein tyrosine phosphatase-deficient “viable motheaten” mice

Ethical considerations constrain the in vivo study of human hemopoietic stem cells (HSC). To overcome this limitation, small animal models of human HSC engraftment have been used. We report the development and characterization of a new genetic stock of IL-2R common γ-chain deficient NOD/LtSz-scid (NOD-scid IL2Rγnull) mice and document their ability to support human mobilized blood HSC engraftment and multilineage differentiation. NOD-scid IL2Rγnull mice are deficient in mature lymphocytes and NK cells, survive beyond 16 mo of age, and even after sublethal irradiation resist lymphoma development. Engraftment of NOD-scid IL2Rγnull mice with human HSC generate 6-fold higher percentages of human CD45+ cells in host bone marrow than with similarly treated NOD-scid mice. These human cells include B cells, NK cells, myeloid cells, plasmacytoid dendritic cells, and HSC. Spleens from engrafted NOD-scid IL2Rγnull mice contain human Ig+ B cells and lower numbers of human CD3+ T cells. Coadministration of human Fc-IL7 fusion protein results in high percentages of human CD4+CD8+ thymocytes as well human CD4+CD8− and CD4−CD8+ peripheral blood and splenic T cells. De novo human T cell development in NOD-scid IL2Rγnull mice was validated by 1) high levels of TCR excision circles, 2) complex TCRβ repertoire diversity, and 3) proliferative responses to PHA and streptococcal superantigen, streptococcal pyrogenic exotoxin. Thus, NOD-scid IL2Rγnull mice engrafted with human mobilized blood stem cells provide a new in vivo long-lived model of robust multilineage human HSC engraftment.

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“…Erythrocytes, leukocytes, and platelets were analyzed using an ADVIA 120 Hematology System (Bayer) as previously described (29 …”

Section: Hematologic and Histopathological Analysesmentioning

confidence: 99%

Human Lymphoid and Myeloid Cell Development in NOD/LtSz-scid IL2Rγnull Mice Engrafted with Mobilized Human Hemopoietic Stem Cells

Shultz

Lyons

Burzenski

et al. 2005

The Journal of Immunology

1,526

1,405

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“…Erythrocytes, leukocytes, and platelets were analyzed using an ADVIA 120 Hematology System (Bayer Corp) as previously described. 27 …”

Section: Hematologic Analyses Of Nonengrafted Micementioning

confidence: 99%

Engraftment of human HSCs in nonirradiated newborn NOD-scid IL2rγnull mice is enhanced by transgenic expression of membrane-bound human SCF

Brehm

Racki

Leif

et al. 2012

Blood

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“…PLC-␤3 functions as a scaffold to interact with Stat5 and SHP-1 via its noncatalytic C-terminal domain to form the multimolecular SPS complex. 19 20 These discrepancies have prompted us to study the regulation of SHP-1. Lyn, a Src family kinase, has been long thought to phosphorylate SHP-1.…”

mentioning

confidence: 99%

Lyn- and PLC-β3–dependent regulation of SHP-1 phosphorylation controls Stat5 activity and myelomonocytic leukemia-like disease

Xiao

Ando

Wang

et al. 2010

Blood

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IntroductionMyelodysplastic/myeloproliferative neoplasms (MDS/MPNs) are de novo clonal myeloid neoplasms that exhibit dysplastic and proliferative features. Four subtypes of human MDS/MPNs have been identified, including chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML). 1 CMML, a prototype of MDS/MPN, is characterized by persistent peripheral blood monocytosis, less than 20% blasts and dysplasia involving 1 or more myeloid lineages. While the cause of CMML is not fully understood yet, as many as 40% of CMML patients exhibit oncogenic mutations of KRAS or NRAS genes. 2 JMML is clinically similar to CMML. Approximately 75% of JMML patients show mutations in KRAS, NRAS, NF1, or PTPN11. These data suggest that hyperactive RAS initiates CMML and JMML. 3 This notion is supported by studies of Nf1, 4 K-ras, 5,6 N-ras, 7 and Ptpn11 8 mutant mice, all of which develop myeloid disorders resembling JMML and CMML. Both CMML and JMML can progress to acute myeloid leukemia (AML) of the myelomonocytic and monocytic subtypes.A small fraction (3.1% versus 19.6% with RAS mutations) of CMML patients harbors FLT3-ITD mutations. A knock-in mouse model harboring an internal tandem duplication (ITD) in the murine Flt3 locus developed MPN with monocytic features resembling CMML. 9 Stat5 is activated by FLT3-ITD 10 and is indispensable for the development of myeloproliferative disease induced by FLT3-ITD. STAT5 and other signaling pathways are activated by the TEL/PDGF␤R fusion protein in CMML patients with the t(5;12) (q33;p13) chromosomal translocation, and STAT5 is critical for this MPN. 11 This raises an immediate question about the role of Stat5 in the pathogenesis of CMML. A cellular characteristic of both JMML and CMML is the hyperesponsiveness to subsaturating concentrations of granulocyte macrophage colonystimulating factor (GM-CSF), 12 and activation of the JAK2-STAT5 pathway is an important signaling event after binding of GM-CSF to the GM-CSF receptor. Indeed, Kotecha et al observed a specific evoked STAT5 signaling signature in JMML, CMML, and M4/5 AML patients in response to low doses of GM-CSF, and levels of STAT5 Tyr 694 phosphorylation were negatively correlated with clinical outcomes. 13 In Nf1 mutant mice, the development of CMML-like disease requires GM-CSF 14 and the common ␤ chain of its receptor. 15 In Ptpn11 E76K transduced bone marrow (BM) cells, phospho-Stat5 levels were dramatically increased. 16 Furthermore, constitutively active Stat5 could induce Ba/F3 cells to differentiate into macrophages. 17 Phospholipase C-␤3 (PLC-␤3) is a member of the PLC-␤ family enzymes that can produce diacylglycerol and inositol 1,4,5-trisphosphate (IP 3 ) downstream of heterotrimeric G proteins. As diacylglycerol can activate several isoforms of protein kinase C, and IP 3 can mobilize Ca 2ϩ , PLC-␤ is implicated in promoting cell proliferation. 18 However, we recently reported that PLC-␤3 Ϫ/Ϫ mice develop a late-onset MPN. 19 The mutant mice have increased numbers of hematopoietic stem cells...

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Mechanisms of anemia in SHP-1 protein tyrosine phosphatase-deficient “viable motheaten” mice

Cited by 20 publications

References 33 publications

Human Lymphoid and Myeloid Cell Development in NOD/LtSz-scid IL2Rγnull Mice Engrafted with Mobilized Human Hemopoietic Stem Cells

Human Lymphoid and Myeloid Cell Development in NOD/LtSz-scid IL2Rγnull Mice Engrafted with Mobilized Human Hemopoietic Stem Cells

Engraftment of human HSCs in nonirradiated newborn NOD-scid IL2rγnull mice is enhanced by transgenic expression of membrane-bound human SCF

Lyn- and PLC-β3–dependent regulation of SHP-1 phosphorylation controls Stat5 activity and myelomonocytic leukemia-like disease

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