The average life span of our country is the longest in the world, and rapid aging is taking place, besides. Therefore the elderly patients with acute myelogenous leukemia (EAML) is increasing. The biological characteristic of EAML is deteriorating internal organs function, and high ratios having the complication of the patient. Leukemic cells in the elderly has the biologic characteristic that non-usual case, for example hypoplastic leukemia, is many, and a case having abnormal chromosomal aberration is also. A social characteristic of EAML is that they are treated at a general hospital such as the municipal hospital not a university hospital, and in many cases the only family is the elderly spouse. Enough understanding of the nation is necessary to overcome such a disadvantageous point and to improve treatment results of EAML.

As for childhood AML, intensification of chemotherapy and advance in supportive care have contributed toward the patient survival. In addition to prevent early death, we have to develop a risk classification and appropriate therapies with updated genomics, especially for the intermediate risk group which has much diversity. Also, new treatment strategies utilizing various molecular-targeted therapies are required. For childhood CML, the possibilities of unknown risks which accompanied by life-long imatinib treatment should be considered. Comparing SCT and imatinib, We need to make an original treatment guideline for child CML. Furthermore, according to the increase of long-term survivors, the late adverse effects showed up. We should aim for "full recovery" and hope to have a long-term follow up and feedback system for the survivors.

The discovery of JAK2 mutation has greatly facilitated the approach to diagnosis of myeloproliferative neoplasms besides chronic myeloid leukemia. Since major causes of morbidity and mortality in polycythemia vera (PV) and essential thrombocythemia (ET) are represented by thrombosis, bleeding, progression to myelofiblosis, and tranfromation to leukemia, risk oriented therapeutic approach is recommended. Established risk factors for cardiovascular events are represented by older age (age over 60) and previous thrombosis. While there are some concerns, the JAK2 mutational status as well as mutant allele burden might be a new surrogate marker for stratified management of PV and ET. Finally, there is a great expectation for novel drugs targeting the constitutively active JAK2/STAT pathway.

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.

Imatinib mesylate, a selective Ab1 tyrosine kinase inhibitor (TKI), is the first choice of therapy for CML and has been dramatically improving the prognosis of patients with chronic phase CML. Now that second generation TKIs including nilotinib and dasatinib is available for imatinib-intolerant or resistant patients, the therapeutic algorithm should be revised and updated. As for AML, a number of clinical trials using TKIs targeting FLT3, whose internal tandem duplication is one of the poor prognostic factors in AML, are in progress and FLT3 inhibitors in combination with chemotherapeutic agents will be promising for relapsed and refractory patients in the near future.

There are several important biological markers in myeloid leukemia. In particular, WT1, FLT3, P-glycoprotein (P-gp) and surface antigens are important biologic markers. When we monitor the treatment of leukemia, WT1 is considered to be an important marker, and has been applied to immune therapy. The abnormality of the genes of FLT3 and expression of P-gp are poor prognostic factors, and their inhibitors are developed in progress. The surface antigen analysis of blast cells is also used in the classification and the treatment strategy decision. Recently, as for the treatment of leukemia, stratification by various kinds of factors has been adopted in many prospective studies. The results of these biological markers are utilized for the stratification.

The disease-specific chromosomal abnormalities can be observed in various hematological malignancies, detected by chromosome analysis and/or genetic testing. Genetic testing enables the accurate diagnosis of the type of leukemia resulting from chromosome translocation and hence is useful for the choice of adequate treatment. Furthermore, genetic testing allows the detection of minimal residual disease (MRD) due to its high sensitivity. In recent years, a lot of information has been gained on the evaluation of MRD, e.g., the amount of MRD corresponding to morphological recurrence or requiring the treatment. Thus, the usefulness of MRD quantification at genetic level by real-time PCR has been established. At present, however, there is no standard laboratory procedure for leukemia genetic testing. Here, the problems related to external precision management of this new test are also discussed.

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.

Hematological malignancy is known to be associated with Down syndrome (DS), neurofibromatosis type 1 (NF1) and congenital bone marrow failure syndromes (CBMFS). Although many responsible germ-cell mutations have been identified, the secondary mutations that are responsible for the development of myelodysplastic syndrome and acute myelogenous leukemia (MDS/AML) have not been determined. Additional chromosomal abnormalities such as monosomy 7 and trisomy 21 are often observed in the progression to MDS/AML, and the critical genes for monosomy 7 have recently been reported. In this review, we briefly present recent findings regarding DS, NF1 and CBMFS with a tendency for malignant transformation; Fanconi anemia, familial platelet disorder with propensity to myeloid malignancy and congenital severe neutropenia.

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.

Leukemogenesis is thought to be a multistep process involving changes in the expression or abnormalities in the function of proteins encorded by a number of genes within the same cell. Such abnormalities affect the balance among cell proliferation, differentiation, and programmed cell death (PCD), and this lead to an expansion of the malignant clone. Apoptosis (type I PCD) and autophagy (type II PCD) are any form of cell death, mediated by an intracellular program, and involved in cell homeostasis. However, the mechanism of apoptosis and autophagy is extremely complex in leukemia cells, and the molecular machinery is still obscure. Therefore, understanding the regulation of apoptotic and autophagic signaling pathways could provide important information for the development of novel therapies in leukemia cells.

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).

Myeloid leukemia in this series corresponds to the myeloid neoplasms of the 4th WHO classification of pathology and genetics of tumor of haematopoietic and lymphoid tissue. The myeloid neoplasms are composed of six categories, which are 1) myeloproliferative neoplasms (MPN), a new category of 2) myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1, 3) myelodysplastic syndrome (MDS)/MPN, 4) MDS, 5) acute myeloid leukemia (AML) and related precursor neoplasms, and 6) acute leukemias of ambiguous lineage. In MPNs without chronic myelogenous leukemia, the genetic marker of JAK2 V617F is added to the diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis. MDS has the new subtype of refractory cytopenia with unilineage dysplasia composed of refractory anemia, refractory neutropenia and refractory thrombocytopenia. AML with t(9; 11) (p22;q23); MLLT3-MLL, AML with t(6;9) (p23; q34); DEK-NUP214, AML with inv(3) (q21q26.2) or t(3; 3) (q21 ; q26.2); RPN1-EVI1 and AML (megakaryoblastic) with t(1; 22) (p13; q13); RBM15-MKL1 are added to the subtype of AML with recurrent genetic abnormalities, and AML with gene mutations of NPM1 and CEBPA are also added as provisional entities of it. The myeloid neoplasms of the 4th WHO classification are comprehensive and seem to be dynamic by incorporating the results of leukemia researches.

Medullary thyroid cancer( MTC) is a neuroendocrine tumor arising from neural-crest-derived, calcitonin-secreting parafollicular C cells within the thyroid. Serum calcitonin (CT) is the most specific and sensitive marker for MTC for both the primary diagnosis and postsurgical follow-up. MTC may occur either sporadically or as part of a hereditary disease such as multiple endocrine neoplasia Type 2A (MEN 2A), multiple endocrine neoplasia Type 2B (MEN 2B) or familial medullary thyroid cancer(FMTC). The primary treatment of MTC is surgical removal of all neoplastic tissue present in the neck and lymph nodes; this should be performed after the careful exclusion of a phenochromocytoma. Mutations in the RET gene are associated with MEN2A, MEN2B and FMTC. Specific RET mutations are associated with each of the MEN2 syndromes and with the aggressiveness of MTC. Consequently, the nature of the RET mutation should guide major management decisions and inform the treatment strategy for MTC.

Epigenetics is defined as the study of changes in gene function that are mitotically and/or meiotically heritable and that dp not entail a change in DNA sequence. Epigenetic regulation of gene expression plays a critical role in development and differentiation, X inactivation, genomic imprinting and several human diseases, including cancer. DNA methylation and histone modifications play an essential role in epigenetic gene expression. In this article, an outline of epigenetics and representative analytic methods are explained. Then, epigenetic alterations and clinical implications of diseases, such as cancer, genomic imprinting-related diseases, and others, are described. The great advance in epigenetic research, from basic to clinical, will bring significant benefits to human health and a broad range of life sciences.

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.