Allogeneic stem cell transplantation represents the most active form of anti-leukemic therapy in acute myeloid leukemia (AML). Advances in the transplant technology, availability of hematopoietic stem cells and supportive care not only have resulted in improved outcomes but also expanded the transplant options. However, post-transplant relapse and transplant-related mortality, especially those associated with allo-immune reaction after transplantation, remain as the leading causes of failure of this therapeutic approach. This review is going to focus on the recent progress to selectively enhance the anti-AML activity of conditioning and post-transplant allo-immune reaction.

Great progress on insight into genetic aberrations of myeloid leukemia via gene expression profiling has led to better understanding of the pathobiology of this heterogeneous disorder. It enabled the development of specific treatment modalities targeted to underlying oncogenic abnormalities, with well established examples of all-trans retinoic acid for the treatment of acute promyelocytic leukemia and imatinib for chronic myeloid leukemia. However, these strategies have not been completely developed yet in that most of brand new targeted therapies have been somewhat far from achieving cure of leukemia and that many problems with regards to drug resistance and recurrence from minimal residual disease remain to be solved. On the other hand, concept of cancer(leukemic) stem cell and its niche has been shedding new light on oncological field these days. This review summarizes the current clinical trials using new targeted therapies and research trends on myeloid leukemia.

Combination chemotherapy with Ara-C and anthracycline anti-leukemia drugs is a standard therapeutics for acute myeloid leukemia (AML) and results in a high rate of complete remission (CR). Several salvage therapies have been established for relapse/refractory AML cases. In addition, a trial of the combination of chemotherapy with gemtuzumab ozogamicin for poor-risk AML is ongoing. The development of a new strategy including combination of conventional anti-leukemia drugs with molecule-targeting reagents might be needed to increase CR rate and cure rates by combination chemotherapy. Development of therapeutics to eradicate leukemia stem cells is also of important for increasing the cure rate of AML.

Chronic myeloid leukemia (CML) is a paradigm for neoplasias that are defined by a unique genetic aberration, the BCR-ABL1 fusion gene. CML is also the best example for molecular target therapy. The development of protein tyrosine kinase inhibitor, imatinib, has entirely changed the strategy of therapy for CML. Nonetheless, many fields of pathogenesis for CML have not been elucidated, such as the mechanisms of blastic crisis, the causes of genetic instability including the inactivation of tumor suppressor genes, and oncogenic signaling pathways downstreams of the BCR-ABL1 fusion gene product. Herein, we review current knowledge on the molecular pathogenesis of CML.

Acute myeloid leukemia (AML) is a malignant hematopoietic neoplasm characterized by clonal proliferation of tumor cells that arise from the hematopoietic stem/progenitor population within the bone marrow. Cytogenetic abnormalities or point mutations of the hematopoiesis-specific genes are frequently found in patients with AML, and these genetic aberrations are closely associated with the pathophysiology of the disease. Molecular pathogenesis of AML has been disclosed through analyses of such gene aberrations, including AML1 and MLL abnormalities, PML-RARA chimeric gene, activating mutations of FLT3, and EVI-1 abnormalities. Through prediction of prognosis and targeted therapy, this knowledge on pathogenesis of AML has been applied to the clinical practice, and further investigation should improve the outcome of therapy for AML in the future.

Myeloid leukemia is a clinically and genetically heterogeneous disease. Cytogenetic studies have revealed specific chromosomal abnormalities, such as translocations, and inversions. Fusion proteins derived from these abnormalities were identified in various subtypes of leukemia. Because most of these fusion proteins were not sufficient to induce leukemia by themselves in mouse models, additional oncogenic events have been thought to be necessary for leukemogenesis. Recently, a hypothesis called "two-hit model" for leukemia has been proposed. Two broad classes of mutations that proliferative or survival advantage of hematopoietic progenitors and impaired differentiation are required for inducing leukemia. In this article, we summarize some typical chromosomal abnormalities or gene mutations associated with myeloid leukemia on the basis of this hypothesis.

Although monoclonal in origin, most tumors appear to contain heterogeneous populations of cancer cells. One possible explanation of this tumor heterogeneity is that human tumors are not merely monoclonal expansions of a single transformed cell, but rather caricatures of normal tissues, and their growth is sustained by cancer stem cells (CSCs). This hierarchy model, first developed for human myeloid leukemias, is supported by mounting evidences today. This conceptual shift has important implications, not only for understanding tumor biology but also for developing and evaluating effective anticancer therapies. We review a history of the development of cancer stem cell concepts in hematology and recent topics of leukemic stem cells (LSCs).

The fundamental principle of the treatment of AML (acute myeloid leukemia) is "total cell kill. " For remission induction, "response-oriented individualized therapy" was developed in Japan. However, the similar response rate was obtained by "set therapy," which became the present standard regimen. Regarding the post-remission therapy, consolidation therapy is conducted without further long-term maintenance/intensification therapy. For poor-risk patients, hematopoietic stem cell transplantation should be considered. To improve the therapeutic efficacy, the development of molecular targeted therapy will be indispensable. As for CML (chronic myeloid leukemia), the development of imatinib has completely changed the treatment strategy. The eradication of CML stem cells is the next challenging issue.

Besides blood flow restoration, neuroprotection is essential for treating strokes at an acute stage. Both neurotrophic factors (NTFs) and free radical scavengers can act as neuroprotective agents with abilities to inhibit cell death and facilitate cell survival under cerebral ischemia. For example, topical application of glial cell line-derived neurotrophic factor (GDNF) remarkably reduced infarct size and brain edema after middle cerebral artery (MCA) occlusion in rats. Reduction in the infarct size was not found to be related to a change in the cerebral blood flow (CBF), but was accompanied by marked reduction in BrdU-positive cells in the affected area after TdT-mediated dUTP-biotin nick end labeling (TUNEL) for caspses. Thus, GDNF elicited a direct protective effect against ischemic brain damage, but without improving CBF. Sendai virus vectors harboring the GDNF gene led to a remarkable reduction in infract volume without affecting regional CBF but reduced the translocation of apoptosis inducible factor (AIF) from the mitochondria to cytoplasm. Regenerative therapy involving neural stem cells which are intrinsically activated or exogenously transplanted, is an important treatment strategy. To facilitate stem cell migration, an artificial scaffold can be implanted into the injured brain for promoting ischemic brain repair. Addition of NTFs greatly enhanced an intrinsic migration or invasion of stem cells into the scaffold: this strategy could be used in the future for enhancing regenerative potential of brain cells after chronic ischemia-induced brain damage.

The four principal epithelial cell lineages (absorptive enterocytes, goblet cells, enteroendocrine cells and Paneth cells) of the adult mouse small intestine derive from multipotent stem cells. Furthermore, the intermediate cells and granule goblet cells are located near the base of crypts of mouse intestine; the former has the characteristics of goblet and Paneth cells and the latter is transformed from the intermediate cells. However, the grounds and the definition for classifing these three cell types (Paneth, intermediate and granule goblet cells) are vague, making it difficult to discuss the structure and a function of those cells. The purpose of this study was to investigate the identification and classification of lysozyme-expressing cells in the mouse small intestinal crypt and their correlation with the morphology of secretory granules and labeling density of immunogold using quantitative immunoelectron microscopy analysis. The results were follows. (1) Paneth cells, intermediate cells and granule goblet cells showed lysozyme immunoreactivity in the electron-dense core of biphasic secretory granules, and therefore lysozyme-exprssing cells were identified in the mouse small intestinal crypt. The sizes of secretory granules were divided into ten groups (every 10%) according to area ratio (core/granule (%)). (2) This distribution of three type cells was classified statistically into "Paneth cell phase": 61% < or = (core/granule (%)), "intermediate cell phase": (core/granule (%)) 21 < or = 60%, "granule goblet cell phase": (core/granule (%)) < or = 20%. (3) Labeling density for lysozyme was commensurate with the size of the central dense core. The Paneth cells had the highest labeling density among the cells. When the transformation from intermediate to granule goblet cell occurred, it happened at the same time that the core of secretory granules gradually shrinks, and the labeling density for lysozyme disappears. (4) The labeling density of immunogold for lysozyme in the small intestine varied at different sites. The labeling density in the Paneth and intermediate cells of the ileal crypt was lower than those of the duodeal and jejunal crypts. (5) In the lysozyme-expressing cells in small intestinal crypt of 2- and 24-month old mouse, the ultrastructure and labeling density did not change.

Cerebral ischemia, a pathological condition in which brain tissue experiences a shortage or lack of glucose and oxygen, provokes an irreversible neurodegenerative disorder that may lead clinically to a progressive dementia and global cognitive deterioration. Accumulating evidence indicates many biochemical cascades that lead ultimately to ischemia-induced cell death. However, the cellular and molecular aspects of cerebral ischemia are not yet fully understood. Since the pattern of pathophysiological alterations is not the same for all cells in the ischemic brain, a good understanding of the cellular and molecular alterations induced by cerebral ischemia is needed to develop strategies for the treatment of stroke. This review summarizes recent advances concerning the pathophysiological alterations caused by cerebral ischemia, focusing on the modification of properties of glutamate receptors, which modification may be linked to the development of cerebral infarction. Furthermore, the effects of hepatocyte growth factor on learning dysfunction and cerebral vessel injury after cerebral ischemia are also summarized. Finally, this review describes a possible ameliorative effect of the injection of exogenous neural progenitor cells on cerebral ischemia-induced learning and memory dysfunction.

Mechanisms of ossification processes, pathological changes, and treatment/assessment of myelopathy symptoms because of ossification of the posterior longitudinal ligament (OPLL) remain obscure. Enchondral ossification process of OPLL was closely associated with degenerative changes of elastic fibers and cartilage formation, together with the appearance of metaplastic hypertrophic cartilage cells and neovascularization. There are differences in expression degrees of cytokines and transcription factors between mixed and localized OPLL. While the chronic compressed spinal cord may have plasticity ; the use of stem cell implants, supplementation of neurotrophic factors, in addition to surgical treatment, may bring a better clinical outcome,encouraging the development of these basic research studies. Assessment using new imaging techniques needs to determine the affected level and judge the severity of symptoms.

Ossification of the longitudinal ligament in the spine is a disorder of unknown cause characterized by ectopic ossification. In the animal models of spinal hyperostosis, the vertebral ligament is gradually replaced by bony tissue forming an osseous bridge around enthesis, and a high turnover osteopenia occurs after the maturation in the trabecular bone of vertebrae. It has been suggested that the recruited vasculature facilitated the filling of the niche with host-derived haematopoietic cells during the ectopic ossification process. Recent data suggest that regulation of hematopoietic and osteogenic stem/progenitor cell populations may contribute to the formation of an ectopic spinal hyperostosis.

A novel hypothesis of carcinogenesis, the "fetal cell carcinogenesis" hypothesis, was established based on molecular evidence of thyroid carcinoma. In this hypothesis, cancer cells are derived directly from the remnants of fetal cells, instead of well-differentiated somatic cells by de-differentiation. For example, thyroid cancer cells are generated from three types of fetal thyroid cell, namely, thyroid stem cells (TSCs), thyroblasts, and prothyrocytes by proliferation without differentiation, which results in producing anaplastic, papillary, and follicular carcinoma, respectively. Genomic alternations, such as RET/PTC and PAX8-PPARgamma1 rearrangements and a mutation in the BRAF gene, play an oncogenic role by preventing thyroid fetal cells from differentiating. Fetal cell carcinogenesis effectively explains recent molecular evidence regarding cancer, including cancer stem cells, and it underscores the importance of identifying a stem cells and clarifying the molecular mechanism of organ development in cancer research. Further, it introduces two important concepts, the reverse approach and stem cell crisis. Analysis of the molecular behavior of a single cell will be a key technique in establishing future laboratory tests. On the other hand, mass analyses such as gene expression profiling, whole genomic scan, and proteomics analysis have definite limitations since they can only provide information based on many cells. In light of these aspects, we started a project to establish FACS-mQ (mRNA quantification after Fluorescence Activated Cell Sorting). In FACS-mQ, cells are sorted by a specific gene expression pattern, and the gene expression profile in sorted cells can be easily analyzed.

Carcinogenic theory is making a unilateral step toward complication, resulting in even apparent chaos. Under such chaotic circumstances, a new theory that stems from the analogy of cancer cells with stem cells, called cancer stem cell theory, is gaining attention. This theory, if correct, necessarily urges two major corrections. One is that such complication may not entirely be the cause of carcinogenesis and, thus, at least partly, nothing more than a consequence. The other is need to create a new framework of cancer therapy. Such a new therapy should allow for long-term symbiosis of a patient with cancer cells; a chemical compound (drug)-based sustainable therapy that directs the dormancy of cancer cells, or converts cancer cells to normal cells (or their resemblances), for example.

Chronic myelogenous leukemia (CML) is associated with the Ph1 chromosome translocation, which produces a chimeric tyrosine-specific kinase gene, the product of the fusion of the BCR gene and the ABL gene. The immune system has long been implicated in the control of CML. We found oligoclonal T cell responses in treated patients with IFN-alpha or leukemic dendritic cells. Also other groups treated chronic phase CML (CP-CML) patients with various leukemic antigen peptides, resulted in apparent immune response and clinical response. Imatinib mesylate is currently used as the first line therapy for CP-CML patients. Although it selectively targets the ABL portion of BCR-ABL protein as a reversible tyrosine kinase inhibitor, it cannot kill the leukemic stem cells of CML. To find a possibility to enhance the immunity in imatinib-treated CML patients by combining it with immunotherapy, we summarized the immune response of innate and adaptive immunity in CML. Development of such immunotherapeutic strategies would be a promising approach to treat the imatinib-treated CML-CP patients.