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Yan-Juan, Tang
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Publications (9 of 9) Show all publications
Tang, Y.-j., Halvarsson, C., Nordigården, A., Kumar, K., Åhsberg, J., Rörby, E., . . . Jönsson, J.-I. (2015). Coexpression of hyperactivated AKT1 with additional genes activated in leukemia drives hematopoietic progenitor cells to cell cycle block and apoptosis. Experimental Hematology, 43(7), 554-564
Open this publication in new window or tab >>Coexpression of hyperactivated AKT1 with additional genes activated in leukemia drives hematopoietic progenitor cells to cell cycle block and apoptosis
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2015 (English)In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 43, no 7, p. 554-564Article in journal (Refereed) Published
Abstract [en]

The phosphatidylinositol 3-kinase/AKT pathway is an integral component of signaling involved in the development of many cancers, including myeloid leukemias such as chronic myeloid leukemia and acute myeloid leukemia (AML). Increased AKT1 activity is frequently seen in AML patients, providing leukemic cells with growth and survival promoting signals. An important aspect of AKT1 function is its involvement in cellular metabolism and energy production. Under some circumstances, strong activation of AKT1 increases oxidative stress, which can cause apoptosis when cells progressively build up excess free radicals. This has been described in hematopoietic cells overexpressing activated AKT1; however, whether this is true in cells coexpressing other genetic events involved in leukemia is not known. This prompted us to investigate the effect of constitutively active AKT1 (myristoylated AKT1) in hematopoietic progenitor cells expressing constitutively active signal transducer and activator of transcription 5, Fms-related tyrosine kinase 3-internal tandem duplication, or antiapoptotic B-cell lymphoma 2. Surprisingly, myristoylated AKT1 was incompatible with proliferation driven by both signal transducer and activator of transcription 5 and Fms-related tyrosine kinase 3-internal tandem duplication, which triggered cell cycle block and apoptosis. Moreover, transplantable cells of B-cell lymphoma 2-transgenic mice were impaired in their engraftment ability to recipient mice when expressing hyperactivated AKT1. This Was linked to AKT1-mediated proapoptotic functions and not to impairment in homing to the bone marrow. Although cells expressing hyperactivated AKT1 displayed higher levels of reactive oxygen species both in vitro and in vivo, the addition of the antioxidant N-acetyl-L-cysteine significantly reduced apoptosis. Taken together, the results indicate that constitutive AKT1 activity is incompatible with growth- and survival-promoting ability of other activated genes in AML. Copyright (C) 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.

Place, publisher, year, edition, pages
Elsevier, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-120213 (URN)10.1016/j.exphem.2015.04.007 (DOI)000356906100007 ()25931014 (PubMedID)
Note

Funding Agencies|Swedish Research Council [2012-2285]; Swedish Cancer Foundation [140316]; Swedish Childrens Cancer Foundation [PR2103-0032]; County Council of Ostergotland; Faculty of Medicine at Linkoping University; Ollie and Elof Ericssons Foundation

Available from: 2015-07-21 Created: 2015-07-20 Last updated: 2017-12-04
Ruud, J., Björk, D., Nilsson, A., Eskilsson, A., Tang, Y.-j., Stroehle, P., . . . Blomqvist, A. (2013). Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells. The FASEB Journal, 27(5), 1973-1980
Open this publication in new window or tab >>Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells
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2013 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, no 5, p. 1973-1980Article in journal (Refereed) Published
Abstract [en]

Loss of appetite is a hallmark of inflammatory diseases. The underlying mechanisms remain undefined, but it is known that myeloid differentiation primary response gene 88 (MyD88), an adaptor protein critical for Toll-like and IL-1 receptor family signaling, is involved. Here we addressed the question of determining in which cells the MyD88 signaling that results in anorexia development occurs by using chimeric mice and animals with cell-specific deletions. We found that MyD88-knockout mice, which are resistant to bacterial lipopolysaccharide (LPS)-induced anorexia, displayed anorexia when transplanted with wild-type bone marrow cells. Furthermore, mice with a targeted deletion of MyD88 in hematopoietic or myeloid cells were largely protected against LPS-induced anorexia and displayed attenuated weight loss, whereas mice with MyD88 deletion in hepatocytes or in neural cells or the cerebrovascular endothelium developed anorexia and weight loss of similar magnitude as wild-type mice. Furthermore, in a model for cancer-induced anorexia-cachexia, deletion of MyD88 in hematopoietic cells attenuated the anorexia and protected against body weight loss. These findings demonstrate that MyD88-dependent signaling within the brain is not required for eliciting inflammation-induced anorexia. Instead, we identify MyD88 signaling in hematopoietic/myeloid cells as a critical component for acute inflammatory-driven anorexia, as well as for chronic anorexia and weight loss associated with malignant disease.

Place, publisher, year, edition, pages
Federation of American Society of Experimental Biology (FASEB), 2013
Keywords
lipopolysaccharide; methylcholanthrene-induced sarcoma; food intake; chimeric mice; Cre-LoxP; inducible cell-specific deletion
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-96147 (URN)10.1096/fj.12-225433 (DOI)000318226100017 ()
Available from: 2013-08-14 Created: 2013-08-14 Last updated: 2017-12-06
Hamzik, N., Tang, Y.-j., Eskilsson, A., Örtegren Kugelberg, U., Ruud, J., Jönsson, J.-I., . . . Nilsberth, C. (2013). Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response. Brain, behavior, and immunity, 33, 123-130
Open this publication in new window or tab >>Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response
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2013 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 33, p. 123-130Article in journal (Refereed) Published
Abstract [en]

Interleukin-6 (IL-6) is critical for the lipopolysaccharide (LPS)-induced febrile response. However, the exact source(s) of IL-6 involved in regulating the LPS-elicited fever is still to be identified. One known source of IL-6 is hematopoietic cells, such as monocytes. To clarify the contribution of hematopoietically derived IL-6 to fever, we created chimeric mice expressing IL-6 selectively either in cells of hematopoietic or, conversely, in cells of non-hematopoietic origin. This was performed by extinguishing hematopoietic cells in wild-type (WT) or IL-6 knockout (IL-6 KO) mice by whole-body irradiation and transplanting them with new stem cells. Mice on a WT background but lacking IL-6 in hematopoietic cells displayed normal fever to LPS and were found to have similar levels of IL-6 protein in the cerebrospinal fluid (CSF) and in plasma and of IL-6 mRNA in the brain as WT mice. In contrast, mice on an IL-6 KO background, but with intact IL-6 production in cells of hematopoietic origin, only showed a minor elevation of the body temperature after peripheral LPS injection. While they displayed significantly elevated levels of IL-6 both in plasma and CSF compared with control mice, the increase was modest compared with that seen in LPS injected mice on a WT background, the latter being approximately 20 times larger in magnitude. These results suggest that IL-6 of non-hematopoietic origin is the main source of IL-6 in LPS-induced fever, and that IL-6 produced by hematopoietic cells only plays a minor role.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Interleukin-6, Hematopoietic cells, Bone marrow transplantation, Fever
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-99401 (URN)10.1016/j.bbi.2013.06.006 (DOI)000324788300016 ()
Note

Funding Agencies|Swedish Research Council|33X-0787968X-2053564X-21463|Swedish Cancer Foundation|4095|Swedish Brain Foundation||Tore Nilsson Foundation||Ake Wiberg Foundation||Langmanska Kulturfonden||Lars Hierta Memorial Foundation||Magn. Bergvall Foundation||County Council of Ostergotland||Harald and Greta Jeansson Foundation||Royal Swedish Academy of Sciences||Foundation of the National Board of Health and Welfare||

Available from: 2013-10-17 Created: 2013-10-17 Last updated: 2017-12-06
Nordigården, A., Halvarsson, C., Tang, Y.-j., Druid, P. & Jönsson, J.-I. (2012). A COMPARATIVE STUDY OF VARIOUS FLT3-ITD MUTATIONS ISOLATED FROM ACUTE MYELOID LEUKEMIA PATIENTS in EXPERIMENTAL HEMATOLOGY, vol 40, issue 8, pp S130-S131. In: EXPERIMENTAL HEMATOLOGY (pp. S130-S131). Elsevier, 40(8)
Open this publication in new window or tab >>A COMPARATIVE STUDY OF VARIOUS FLT3-ITD MUTATIONS ISOLATED FROM ACUTE MYELOID LEUKEMIA PATIENTS in EXPERIMENTAL HEMATOLOGY, vol 40, issue 8, pp S130-S131
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2012 (English)In: EXPERIMENTAL HEMATOLOGY, Elsevier , 2012, Vol. 40, no 8, p. S130-S131Conference paper, Published paper (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
Elsevier, 2012
Series
EXPERIMENTAL HEMATOLOGY, ISSN 0301-472X
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-80785 (URN)000307319600202 ()
Available from: 2012-08-30 Created: 2012-08-30 Last updated: 2012-08-30
Tang, Y.-j., Halvarsson, C., Eliasson, P. & Jönsson, J.-I. (2012). Letter: Hypoxic and normoxic in vitro cultures maintain similar numbers of long-term reconstituting hematopoietic stem cells from mouse bone marrow [Letter to the editor]. Experimental Hematology, 40(11), 879-881
Open this publication in new window or tab >>Letter: Hypoxic and normoxic in vitro cultures maintain similar numbers of long-term reconstituting hematopoietic stem cells from mouse bone marrow
2012 (English)In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 40, no 11, p. 879-881Article in journal, Letter (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
Elsevier, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85627 (URN)10.1016/j.exphem.2012.07.005 (DOI)000310182400001 ()
Available from: 2012-11-26 Created: 2012-11-26 Last updated: 2018-10-18
Nordigården, A., Tang, Y., Halvarsson, C. & Jönsson, J.-I.A comparative study of various FLT3-ITDs in relation to function and signaling.
Open this publication in new window or tab >>A comparative study of various FLT3-ITDs in relation to function and signaling
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Internal tandem duplications (ITD) in the FMS like tyrosine kinase (FLT3) receptor are one of the most common classes of mutations in acute myeloid leukemia (AML), which presence indicates a poor prognosis. Lengths of FLT3-ITD mutations found in patients can vary from 3 up to hundreds of nucleotides and may be located either in the juxtamembrane domain or the tyrosine kinase-1 domain (TKD1). There are contradicting opinions whether the length of the ITD has an impact on the clinical situation and whether tyrosines duplicated are of any significance for oncogenic signaling. Considering the substantial differences in lengths as well as the variability of start and end points of ITDs, we have performed a study of various FLT3-ITD mutations isolated from AML-patients. The ITD region from leukemic blasts of nine AML patients were sequenced and cloned by PCR into the human wildtype FLT3 cDNA, inserted to a retroviral GFP-containing vector. The hematopoietic progenitor cell line FDC-P1 was used to elucidate the impact of the different ITDs on growth, survival, signal transduction, and resistance to the FLT3-targeting inhibitor PKC412. Interestingly, the shortest and the longest ITDs were two of the three mutations that lead to the poorest survival of cells upon cytokine-deprivation, indicating that ITD size may not influence the transforming potential of cells. Furthermore one ITD that starts and ends relatively 3´ positioned, and comprises the 5´-part of the TKD1 showed both a survival advantage in starvation experiments and a significantly higher proliferation potential in comparison to several other mutations. Two other ITDs spanning this region, but with more 5´localized starting points, displayed less sensitivity to PKC412 treatment. However, this was not associated to STAT5 activity and MCL-1 upregulation as suggested by previous report. Taken together, this study suggests that different FLT3-ITD mutations may induce distinct signaling and response towards FLT3 targeting drugs, dependent of FLT3-ITD composition and not length.

Keywords
FLT3-ITD, proliferation, apoptosis, tyrosine kinase inhibitor, resistance
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-88200 (URN)
Available from: 2013-01-31 Created: 2013-01-31 Last updated: 2013-01-31Bibliographically approved
Tang, Y., Halvarsson, C., Nordigården, A., Åhsberg, J., Wong, W. M. & Jönsson, J.-I.Hyperactivated AKT is incompatible with survival when coexpressed with additional oncogenes and drives hematopoietic stem and progenitor cells to cell cycle inhibition and apoptosis.
Open this publication in new window or tab >>Hyperactivated AKT is incompatible with survival when coexpressed with additional oncogenes and drives hematopoietic stem and progenitor cells to cell cycle inhibition and apoptosis
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The PI3K-AKT signaling pathway plays an important role in cell growth and metabolism. Increased AKT activity is frequently seen in patients with acute myeloid leukemia (AML), providing leukemic cells with both growth-promoting and survival signals involved in the transformation process. In AML up to 30% of all patients carry activating mutations in the tyrosine kinase receptor FLT3, leading to activation of the PI3K/AKT pathway as well as STAT5. Here, we investigated the effect of hyperactivated AKT (myristylated AKT) by retroviral transfer to hematopoietic progenitor cells coexpressing STAT5, FLT3-ITD, or antiapoptotic Bcl-2. AKT was unable to relieve cytokine-dependence. Surprisingly, uncontrolled AKT activity was linked to accumulation of cells in the G0 stage of the cell cycle and increased cell numbers became apoptotic. Hyperactivated AKT was incompatible with STAT5-driven proliferation and triggered apoptosis. The same was true also in FLT3-ITDexpressing progenitor cells of transgenic mice. Transplantable hematopoietic stem cells of wildtype and Bcl-2 transgenic mice were impaired in their engraftment ability to recipient mice when expressing hyperactivated AKT. This was linked to AKT-mediated pro-apoptotic functions and not due to effects on homing or migration. Cells expressing hyperactivated AKT displayed higher levels of reactive oxygen species. However, the addition of the antioxidant N-acetyl-L-lysine significantly reduced apoptosis. Taken together, the results indicate that constitutive AKT activity is incompatible with the growth- and survivalpromoting ability of FLT3-ITD and its downstream targets. These findings may provide a novel tool to intervene with AKT activity in leukemia.

Keywords
Hematopoiesis, transplantation, oncogenes, AKT, STAT5, FLT3-ITD, Bcl-2, apoptosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-88201 (URN)
Available from: 2013-01-31 Created: 2013-01-31 Last updated: 2013-01-31
Hamzic, N., Tang, Y., Eskilsson, A., Kugelberg, U., Ruud, J., Jönsson, J.-I., . . . Nilsberth, C.Interleukin-6 produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response.
Open this publication in new window or tab >>Interleukin-6 produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Interleukin-6 (IL-6) is critical for the lipopolysaccharide (LPS)-induced febrile response. However, the exact source(s) of IL-6 involved in regulating the LPS-elicited fever is still to be identified. One known source of IL-6 is hematopoietic cells, such as monocytes. To clarify the contribution of hematopoietically derived IL-6 to fever, we created chimeric mice expressing IL-6 either in cells of hematopoietic or, conversely, in cells of non-hematopoietic origin. This was performed by extinguishing hematopoetic cells in wild-type (WT) or IL-6 knockout (IL-6 KO) mice by whole-body irradiation and transplanting them with new stem cells. Mice lacking IL-6 in hematopoietic cells displayed normal fever to LPS and were found to have similar levels of IL-6 in the cerebrospinal fluid (CSF) and in plasma as well as similar expression of the IL-6 gene in the brain as WT mice. In contrast, IL-6 KO mice, with intact IL-6 production in cells of hematopoietic origin, only showed a minor elevation of the body temperature after peripheral LPS injection. While they displayed significantly elevated levels of IL-6 both in plasma and CSF compared with control mice, the increase was modest compared with that seen in LPS injected mice on WT background, the latter being approximately 20 times larger in magnitude. These results suggest that IL-6 of nonhematopoietic origin is the main source of IL-6 in LPS-induced fever, and that IL-6 produced by hematopoietic cells only plays a minor role.

Keywords
Interleukin-6, hematopoietic cells, bone marrow transplantation, fever
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-87452 (URN)
Available from: 2013-01-18 Created: 2013-01-18 Last updated: 2016-05-04Bibliographically approved
Ruud, J., Björk Wilhelms, D., Nilsson, A., Eskilsson, A., Yan-Juan, T., Bäckhed, F., . . . Blomqvist, A.MyD88 in hematopoietic cells, but not in cerebrovascular endothelial cells or neural cells, is critical for inflammation- and cancer-induced loss of appetite.
Open this publication in new window or tab >>MyD88 in hematopoietic cells, but not in cerebrovascular endothelial cells or neural cells, is critical for inflammation- and cancer-induced loss of appetite
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Loss of appetite concomitant with reduced food intake is a hallmark of both acute and chronic inflammatory diseases. Yet, despite extensive investigations, the underlying mechanisms remain undefined. Here we addressed this issue using mice lacking MyD88, critical for Tolllike and IL-1 receptor family signaling, generally or in specific cell types. Ubiquitous null deletions conferred complete resistance to bacterial lipopolysaccharide (LPS) induced anorexia, but this resistance was lost when knock-out mice subjected to whole-body irradiation to delete hematopoietic cells were transplanted with wild-type bone-marrow. In line with this observation, mice lacking MyD88 in hematopoietic cells were largely protected against LPS-induced anorexia, whereas mice with abrogated MyD88 signaling in neural cells, being leaner and smaller, developed anorexia of similar magnitude as wild-type littermates. The effect of hematopoietic MyD88-deletion on feeding seemed however partially dissociated from the effect on body weight, since LPS triggered weight loss, although attenuated, in these mutants. Furthermore, MyD88 deficiency in the cerebrovascular endothelium affected neither LPS-induced anorexia nor weight loss. In a model for the cancer anorexia-cachexia syndrome, inactivation of MyD88 in hematopoietic cells strongly impaired the anorexia development and protected against body weight loss. These findings identify hematopoietic cells as a critical nexus for acute inflammatory driven anorexia as well as for chronic anorexia associated with malignant disease.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77753 (URN)
Available from: 2012-05-28 Created: 2012-05-28 Last updated: 2012-05-28Bibliographically approved
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