IntroductionMyelodysplastic syndrome (MDS) is a slowly progressing leukemic disorder that predominantly affects elderly people. 1,2 Individuals with MDS exhibit cytopenia in at least one lineage of peripheral blood (PB) cells. However, the bone marrow (BM) of many affected individuals is hyper-to normocellular, suggesting the presence of ineffective hematopoiesis. Another characteristic feature of MDS is the dysplasia of at least one lineage (myeloid, erythroid, or megakaryocyte-platelet lineage) of BM cells, such as neutrophils with pseudo-Pelger anomaly, hypersegmented neutrophils, ringed sideroblasts, and micromegakaryocytes. 3 The clinical course of MDS can be divided into several phases. Patients in the indolent, chronic phase exhibit a decrease in the number of PB cells and are diagnosed with either refractory anemia (RA) or RA with ringed sideroblasts (RARS). Individuals with dysplastic change in BM and monocytosis in PB are diagnosed with chronic myelomonocytic leukemia (CMMoL). After a variable interval, however, some individuals with MDS undergo a progressive transformation to overt leukemia. As the number of blast cells increases, the patients are diagnosed with RA with an excess of blasts (RAEB; 5%-19% blasts in BM), RAEB in transformation (RAEB-t; 20%-29% blasts in BM), and, finally, MDS-associated acute leukemia (Ͼ 20% blasts in BM).MDS-associated leukemia is rarely cured by conventional chemotherapy. Intensive treatment with anticancer drugs often results in prolonged myelosuppression, which is one of the main causes of disease-related death. 4 Individuals with acute leukemia that results from MDS therefore have a poor prognosis, which contrasts with the somewhat better outcome of de novo acute myeloid leukemia (AML) in this older group of patients. It is thus essential to differentiate MDS-associated leukemia from de novo AML to select the optimal therapeutic strategy.This task is complicated, however, by the fact that some patients with de novo AML may exhibit dysplastic changes in BM during the course of their disease. [5][6][7] It is thus extremely difficult to diagnose elderly individuals with overt leukemia if their BM exhibits dysplasia. The occurrence of a period of cytopenia before the development of leukemia indicates that the patient should be treated for MDS-associated leukemia. Without the clinical history, however, there are currently few other criteria with which to differentiate MDS-associated leukemia from de novo AML with The development of DNA microarrays or DNA chips has revolutionized the analysis of gene expression profiles. Such DNA microarrays can contain tens of thousands of test complementary DNAs (cDNAs) or oligonucleotides and, with a single hybridization step, allow a systematic comparison of the expression of the corresponding genes between 2 given samples. 8 The completion of the human genome sequencing project will increase further the analytical power of this technology. The use of DNA microarrays has already allowed the identification of candidate mammalian genes ...

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Iron-overloaded (IO) mice did not show significant defects in the hematopoietic data of the peripheral blood. Myeloid progenitor cells in the bone marrow were increased in IO mice, but the number and function of the erythroid progenitors and hematopoietic stem cells were not significantly affected. However, bone marrow transplantation from normal donors to IO recipients showed delayed hematopoietic reconstitution, which indicates that excess iron impacts the hematopoietic microenvironment negatively. Microarray and quantitative RT-PCR analyses on the bone marrow stromal cells demonstrated remarkably reduced expression of CXCL12, VCAM-1, Kit-ligand, and IGF-1 in the iron-overloaded mice. In addition, erythropoietin and thrombopoietin levels were significantly suppressed, and increased oxidative stress was observed in the IO bone marrow and liver. Consequently, our findings indicate that excess iron can damage bone marrow stromal cells and other vital organs, disrupting hematopoiesis presumably by increased oxidative stress.

Summary. Myelodysplastic syndrome (MDS) is a clonal disorder of haematopoietic stem cells. Despite the high incidence of MDS in the elderly, effective treatment of individuals in its advanced stages is problematic. DNA microarray analysis is a potentially informative approach to the development of new treatments for MDS. However, a simple comparison of 'transcriptomes' of bone marrow mononuclear cells among individuals at distinct stages of MDS would result in the identification of genes whose expression differences only reflect differences in the proportion of MDS blasts within bone marrow. Such a 'population shift' effect has now been avoided by purification of haematopoietic stem-like cells that are positive for the cell surface marker AC133 from the bone marrow of healthy volunteers and 30 patients at various stages of MDS. Microarray analysis with the AC133 + cells from these individuals resulted in the identification of sets of genes with expression that was specific to either indolent or advanced stages of MDS. The former group of genes included that for PIASy, which catalyses protein modification with the ubiquitin-like molecule SUMO. Induction of PIASy expression in a mouse myeloid cell line induced apoptosis. A loss of PIASy expression may therefore contribute directly to the growth of MDS blasts and stage progression.

The murine sak gene encodes a putative serine-threonine kinase which is homologous to the members of the Plk/Polo family. Although Sak protein is presumed to be involved in cell growth mechanism, efforts have failed to demonstrate its kinase activity. Little has been, therefore, elucidated how Sak is regulated and how Sak contributes to cell proliferation. Tec is a cytoplasmic protein-tyrosine kinase (

Key Points The cost of TKI for treatment of CML can be substantially saved by treatment discontinuation in patients who achieved DMR. Starting treatment with imatinib is the most cost-effective strategy even after incorporation of treatment discontinuation.

Apoptosis is involved in both the cellular and humoral immune system destroying tumors. An apoptosis-inducing factor from HL-60 myeloid leukemia cells was obtained, purified, and sequenced. The protein found has been identified as a human complement factor B-derived fragment Bb, although it is known that factor B is able to induce apoptosis in several leukemia cell lines. Monoclonal antibodies against fragment Ba and Bb inhibited the apoptotic activity of factor B. When the purified fragment Bb was used for apoptosis induction, only the anti-Bb antibody inhibited Bb-induced apoptosis, and not the anti-Ba antibody. The apoptosis-inducing activity was found to be enhanced under conditions facilitating the formation of Bb. Blocking TNF/TNFR or FasL/Fas interactions did not interfere with the factor B-induced apoptosis. CD11c (iC3bR) acts as the main subunit of a heterodimer binding to fragment Bb in the apoptosis pathway, and the factor B-derived fragment Bb was found to possess the previously unknown function of inducing apoptosis in leukemic cells through a suicide mechanism of myeloid lineage cells during the differentiation stage.