Subject(s)
Antineoplastic Agents/pharmacology , Benzodioxoles/pharmacology , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Membrane Microdomains/drug effects , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Quinazolines/pharmacology , Animals , Cell Line, Tumor , Disease Models, Animal , Humans , Membrane Potential, Mitochondrial , Mice , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Reactive Oxygen Species/metabolism , Xenograft Model Antitumor AssaysABSTRACT
CD45 is a pan-leukocyte protein with tyrosine phosphatase activity involved in the regulation of signal transduction in hematopoiesis. Exploiting CD45 KO mice and lentiviral shRNA, we prove the crucial role that CD45 plays in acute myeloid leukemia (AML) development and maintenance. We discovered that CD45 does not colocalize with lipid rafts on murine and human non-transformed hematopoietic cells. Using a mouse model, we proved that CD45 positioning within lipid rafts is modified during their oncogenic transformation to AML. CD45 colocalized with lipid rafts on AML cells, which contributes to elevated GM-CSF signal intensity involved in proliferation of leukemic cells. We furthermore proved that the GM-CSF/Lyn/Stat3 pathway that contributes to growth of leukemic cells could be profoundly affected, by using a new plasma membrane disrupting agent, which rapidly delocalized CD45 away from lipid rafts. We provide evidence that this mechanism is also effective on human primary AML samples and xenograft transplantation. In conclusion, this study highlights the emerging evidence of the involvement of lipid rafts in oncogenic development of AML and the targeting of CD45 positioning among lipid rafts as a new strategy in the treatment of AML.
Subject(s)
Leukemia, Myeloid, Acute/metabolism , Leukocyte Common Antigens/metabolism , Membrane Microdomains/metabolism , Animals , Carcinogenesis/genetics , Cell Line, Tumor , Female , Genetic Vectors , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Hematopoiesis/genetics , Humans , Lentivirus/genetics , Leukemia, Myeloid, Acute/pathology , Leukocyte Common Antigens/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , RNA, Small Interfering/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction , Xenograft Model Antitumor AssaysSubject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukocyte Common Antigens/physiology , Molecular Targeted Therapy , Quinoxalines/therapeutic use , Antineoplastic Agents/pharmacology , Granulocyte-Macrophage Colony-Stimulating Factor/physiology , Humans , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/metabolism , Leukocyte Common Antigens/antagonists & inhibitors , Leukocyte Common Antigens/immunology , Quinoxalines/pharmacology , Signal Transduction/immunologyABSTRACT
The hematopoietic system declines with age. Myeloid-biased differentiation and increased incidence of myeloid malignancies feature aging of hematopoietic stem cells (HSCs), but the mechanisms involved remain uncertain. Here, we report that 4-mo-old mice deleted for transcription intermediary factor 1γ (Tif1γ) in HSCs developed an accelerated aging phenotype. To reinforce this result, we also show that Tif1γ is down-regulated in HSCs during aging in 20-mo-old wild-type mice. We established that Tif1γ controls TGF-ß1 receptor (Tgfbr1) turnover. Compared with young HSCs, Tif1γ(-/-) and old HSCs are more sensitive to TGF-ß signaling. Importantly, we identified two populations of HSCs specifically discriminated by Tgfbr1 expression level and provided evidence of the capture of myeloid-biased (Tgfbr1(hi)) and myeloid-lymphoid-balanced (Tgfbr1(lo)) HSCs. In conclusion, our data provide a new paradigm for Tif1γ in regulating the balance between lymphoid- and myeloid-derived HSCs through TGF-ß signaling, leading to HSC aging.
