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      Regulation of myeloid leukemia by the cell fate determinant Musashi

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          Abstract

          Chronic myelogenous leukemia (CML) can progress from an indolent chronic phase to an aggressive blast crisis phase 1 but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML 2, 3 to show that disease progression is regulated by the Musashi-Numb signaling axis 4, 5. Specifically, we find that chronic phase is marked by high and blast crisis phase by low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced phase disease in vivo. As a possible explanation for the decreased levels of Numb in blast crisis, we show that NUP98-HOXA9, an oncogene associated with blast crisis CML 6, 7, can trigger expression of the RNA binding protein Musashi2 (Msi2) which in turn represses Numb. Importantly, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally, we show that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poorer prognosis. These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for therapy of aggressive leukemias.

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          Most cited references36

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          Is Open Access

          Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma

          Background Recently, a small population of cancer stem cells in adult and pediatric brain tumors has been identified. Some evidence has suggested that CD133 is a marker for a subset of leukemia and glioblastoma cancer stem cells. Especially, CD133 positive cells isolated from human glioblastoma may initiate tumors and represent novel targets for therapeutics. The gene expression and the drug resistance property of CD133 positive cancer stem cells, however, are still unknown. Results In this study, by FACS analysis we determined the percentage of CD133 positive cells in three primary cultured cell lines established from glioblastoma patients 10.2%, 69.7% and 27.5%, respectively. We also determined the average mRNA levels of markers associated with neural precursors. For example, CD90, CD44, CXCR4, Nestin, Msi1 and MELK mRNA on CD133 positive cells increased to 15.6, 5.7, 337.8, 21.4, 84 and 1351 times, respectively, compared to autologous CD133 negative cells derived from cell line No. 66. Additionally, CD133 positive cells express higher levels of BCRP1 and MGMT mRNA, as well as higher mRNA levels of genes that inhibit apoptosis. Furthermore, CD133 positive cells were significantly resistant to chemotherapeutic agents including temozolomide, carboplatin, paclitaxel (Taxol) and etoposide (VP16) compared to autologous CD133 negative cells. Finally, CD133 expression was significantly higher in recurrent GBM tissue obtained from five patients as compared to their respective newly diagnosed tumors. Conclusion Our study for the first time provided evidence that CD133 positive cancer stem cells display strong capability on tumor's resistance to chemotherapy. This resistance is probably contributed by the CD133 positive cell with higher expression of on BCRP1 and MGMT, as well as the anti-apoptosis protein and inhibitors of apoptosis protein families. Future treatment should target this small population of CD133 positive cancer stem cells in tumors to improve the survival of brain tumor patients.
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            Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia.

            Ruibao Ren (2005)
            Imatinib, a potent inhibitor of the oncogenic tyrosine kinase BCR-ABL, has shown remarkable clinical activity in patients with chronic myelogenous leukaemia (CML). However, this drug does not completely eradicate BCR-ABL-expressing cells from the body, and resistance to imatinib emerges. Although BCR-ABL remains an attractive therapeutic target, it is important to identify other components involved in CML pathogenesis to overcome this resistance. What have clinical trials of imatinib and studies using mouse models for BCR-ABL leukaemogenesis taught us about the functions of BCR-ABL beyond its kinase activity, and how these functions contribute to CML pathogenesis?
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              Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision.

              The transcription factor recombination signal binding protein-J (RBP-J) functions immediately downstream of the cell surface receptor Notch and mediates transcriptional activation by the intracellular domain of all four kinds of Notch receptors. To investigate the function of RBP-J, we introduced loxP sites on both sides of the RBP-J exons encoding its DNA binding domain. Mice bearing the loxP-flanked RBP-J alleles, RBP-J(f/f), were mated with Mx-Cre transgenic mice and deletional mutation of the RBP-J gene in adult mice was induced by injection of the IFN-alpha inducer poly(I)-poly(C). Here we show that inactivation of RBP-J in bone marrow resulted in a block of T cell development at the earliest stage and increase of B cell development in the thymus. Lymphoid progenitors deficient in RBP-J differentiate into B but not T cells when cultured in 2'-deoxyguanosine-treated fetal thymic lobes by hanging-drop fetal thymus organ culture. Competitive repopulation assay also revealed cell autonomous deficiency of T cell development from bone marrow of RBP-J knockout mouse. Myeloid and B lineage differentiation appears normal in the bone marrow of RBP-J-inactivated mice. These results suggest that RBP-J, probably by mediating Notch signaling, controls T versus B cell fate decision in lymphoid progenitors.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                7 June 2010
                18 July 2010
                5 August 2010
                1 February 2011
                : 466
                : 7307
                : 765-768
                Affiliations
                [1 ]Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27710
                [2 ]Department of Pathology Duke University Medical Center, Durham, NC, 27710
                [3 ]Department of Haematology, Imperial College London, Hammersmith Hospital, London, W12 0NN
                [4 ]Division of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
                [5 ]Department of Haematology, Singapore General Hospital, Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore
                [6 ]Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109
                [7 ]James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, NY 14642
                Author notes
                [§]

                These authors contributed equally to this work

                Author Contributions: T.I. and H.Y.K. designed the research, performed the majority of the experiments and helped write the paper. B.Z., K.L.C., J.B., W.L. and C.Z. provided experimental data and help, A.L. provided histopathological analysis, C.T.J., G.G., L.F., J.G., H.G., S-H.K., D-W.K. and C.C. provided human patient samples and experimental advice, T.I., H.Y.K., G.G. and B.Z. defined gene expression in patient samples by PCR and V.G.O. and J.P.R. carried out all microarray and patient outcomes analyses. T.R. conceived of the project, planned and guided the research, and wrote the paper.

                [* ]Correspondence should be addressed to T. R. ( t.reya@ 123456duke.edu )
                Article
                nihpa206659
                10.1038/nature09171
                2918284
                20639863
                1252ce92-af3e-40bf-8c40-436f59a33f20

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                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: Office of the Director : NIH
                Award ID: U19 AI067798-050006 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: Office of the Director : NIH
                Award ID: U19 AI067798-040006 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
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                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
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                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
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                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
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