Targeting of cancer stem cells is believed to be essential for curative therapy of cancers, but supporting evidence is limited. Few selective target genes in cancer stem cells have been identified. Here we identify the arachidonate 5-lipoxygenase (5-LO) gene (Alox5) as a critical regulator for leukemia stem cells (LSCs) in BCR-ABL-induced chronic myeloid leukemia (CML). In the absence of Alox5, BCR-ABL failed to induce CML in mice. This Alox5 deficiency caused impairment of the function of LSCs but not normal hematopoietic stem cells (HSCs) through affecting differentiation, cell division, and survival of long-term LSCs (LT-LSCs), consequently causing a depletion of LSCs and a failure of CML development. Treatment of CML mice with a 5-LO inhibitor also impaired the function of LSCs similarly by affecting LT-LSCs, and prolonged survival. These results demonstrate that a specific target gene can be found in cancer stem cells and its inhibition can completely inhibit the function of these stem cells.
Philadelphia chromosome-positive (Ph þ ) chronic myeloid leukemia (CML) induced by the BCR-ABL oncogene is believed to be developed from leukemic stem cells (LSCs), and we have previously shown in mice that LSCs for CML express the same cell surface markers that are also expressed on normal hematopoietic stem cells (HSCs). Although the inhibition of BCR-ABL kinase activity by imatinib is highly effective in treating human Ph þ CML in chronic phase, it is difficult to achieve molecular remission of the disease, suggesting that LSCs remain in patients. In this study, we find that following imatinib treatment, LSCs not only remained but also accumulated increasingly in bone marrow of CML mice. This insensitivity of LSCs to imatinib was not because of the lack of BCR-ABL kinase inhibition by imatinib, and proliferating leukemic cells derived from LSCs were still sensitive to growth inhibition by imatinib. These results identify an LSC survival pathway that is not inhibited by imatinib. Furthermore, we show that b-catenin in the Wnt signaling pathway is essential for survival and self-renewal of LSCs, providing a new strategy for targeting these cells.
IntroductionThe human Philadelphia chromosome (Ph) arises from a reciprocal translocation between chromosome 9 and 22, resulting in the formation of chimeric BCR-ABL oncogene. BCR-ABL encodes a constitutively activated, oncogenic tyrosine kinase. 1 Ph ϩ leukemia induced by BCR-ABL includes chronic myeloid leukemia (CML) and B-cell acute lymphoid leukemia (B-ALL). The BCR-ABL kinase inhibitor imatinib mesylate induces a complete hematologic and cytogenetic response in the majority of chronic-phase CML patients 2 but is unable to completely eradicate BCR-ABLexpressing leukemic cells, 3,4 suggesting that leukemia stem cells are not eliminated. Over time, patients frequently become drugresistant and develop progressive disease despite continued treatment. [5][6][7] Moreover, B-ALL is less sensitive to imatinib, suggesting that inhibition of BCR-ABL kinase activity is not enough to suppress B-ALL development. New therapeutic strategies need to be developed for Ph ϩ leukemia.Tumors progress to more advanced stages after acquiring additional genetic alterations, and inactivation of tumor suppressor genes are common in human cancers. Phosphatase and tensin homolog (PTEN) 8 is often deleted or inactivated in many tumor types, including glioblastoma, 9 endometrial carcinoma, 10 and lymphoid malignancies. 11 PTEN is a phosphatase that dephosphorylates phosphatidylinositol-3-trisphosphate. 12,13 Phosphatidylinositol-3-trisphosphate is a direct product of phosphoinositide 3-kinase (PI3K) activity and plays a critical role in the regulation of cell survival and growth by activating the Ser/Thr protein kinase PDK1 and its downstream target Akt. 14,15 Activated Akt mediates several well-described PI3K responses that include cell survival and growth, cellular metabolism, angiogenesis, and cell migration.Mice with a complete null mutation of Pten develop early embryonic lethality at E9.5. [16][17][18] Pten-heterozygous mice die within 1 year after birth, and survivors develop a broad range of tumors, including mammary, thyroid, endometrial, and prostate cancers, [16][17][18] as well as autoimmunity related to Fas-mediated response. 19 Mice with the tissuespecific deletion of Pten using the Cre-loxP system have become available for studying physiologic functions of Pten in adult tissues and organs. 20,21 For example, mice with Pten deletion in adult hematopoietic cells develop and die of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). 22 Akt1 is a major downstream signaling molecule of PTEN and is activated after PTEN is mutated in human cancers. Investigators in a recent study 23 showed that the deficiency of Akt1 is sufficient to suppress the development of several types of tumors in Ptenheterozygous mice, including prostate cancer, endometrial carcinoma, thyroid neoplasia, intestinal polyps, and lymphoid hyperplasia. Moreover, rapamycin, which directly inhibits the Akt downstream molecule mammalian target of rapamycin (mTOR), effectively inhibits survival and proliferation of AML cells from PTEN fl/fl ;Mx-1...
Omacetaxine mepesuccinate (formerly homoharringtonine) is a molecule with a mechanism of action that is different from tyrosine kinase inhibitors and its activity in chronic myeloid leukemia (CML) seems to be independent of BCR-ABL mutation status. Using BCR-ABL-expressing myelogenous and lymphoid cell lines and mouse models of CML and B cell acute lymphoblastic leukemia (B-ALL) induced by wild type BCR-ABL or T315I mutant-BCR-ABL, we evaluated the inhibitory effects of omacetaxine on CML and B-ALL. We demonstrated that more than 90% of the leukemic stem cells were killed after treatment with omacetaxine in vitro. In contrast, less than 9% or 25% of the leukemic stem cells were killed after treating with imatinib or dasatinib, respectively. After 4 days of treatment of CML mice with omacetaxine, Gr-1+myeloid leukemia cells decreased in the peripheral blood of the treated CML mice. In the omacetaxine treated B-ALL mice, only 0.8% B220+leukemia cells were found in peripheral blood, compared with 34% B220+leukemia cells in the placebo group. Treatment with omacetaxine decreased the number of leukemia stem cells and prolonged survival of mice with BCR-ABL induced CML or B-ALL.
Although alveolar epithelial type II cells (AECII) perform substantial roles in the maintenance of alveolar integrity, the extent of their contributions to immune defense is poorly understood. Here, we demonstrate that AECII activates alveolar macrophages (AM) functions, such as phagocytosis using a conditioned medium from AECII infected by P. aeruginosa. AECII-derived chemokine MCP-1, a monocyte chemoattractant protein, was identified as a main factor in enhancing AM function. We proposed that the enhanced immune potency of AECII may play a critical role in alleviation of bacterial propagation and pneumonia. The ability of phagocytosis and superoxide release by AM was reduced by MCP-1 neutralizing antibodies. Furthermore, MCP-1−/− mice showed an increased bacterial burden under PAO1 and PAK infection vs. wt littermates. AM from MCP-1−/− mice also demonstrated less superoxide and impaired phagocytosis over the controls. In addition, AECII conditioned medium increased the host defense of airway in MCP-1−/− mice through the activation of AM function. Mechanistically, we found that Lyn mediated NFκB activation led to increased gene expression and secretion of MCP-1. Consequently Lyn−/− mice had reduced MCP-1 secretion and resulted in a decrease in superoxide and phagocytosis by AM. Collectively, our data indicate that AECII may serve as an immune booster for fighting bacterial infections, particularly in severe immunocompromised conditions.
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