Classification and prognostic evaluation of myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by dysplasia in one or more cell lines and increased risk of development of acute myeloid leukemia (AML). The current diagnostic approach to MDS includes peripheral blood and bone marrow morphology to evaluate abnormalities of peripheral blood cells and hematopoietic precursors; bone marrow biopsy to assess marrow cellularity, fibrosis, and topography; and cytogenetics to identify non-random chromosomal abnormalities. The 2008 World Health Organization (WHO) classification currently provides the best diagnostic approach to MDS and also has considerable prognostic relevance. The WHO classification-based prognostic scoring system (WPSS) is able to classify MDS patients into five risk groups showing different survivals and probabilities of leukemic evolution. The WPSS is able to predict survival and leukemia progression at any time during follow-up, and can therefore be used for implementing risk-adapted treatment strategies in patients with primary MDS. Since comorbidities have a significant impact on the outcome of patients with MDS, accounting for both disease status and comorbid conditions considerably improves risk stratification.     

Magnetic resonance imaging of bone marrow versus bone marrow biopsy in malignant lymphoma

Bone marrow involvement is a frequent finding in malignant lymphoma. Bone marrow biopsy of the posterior iliac crest is routinely performed for staging. Abnormal magnetic resonance imaging (MRI) signals of bone marrow was also reported to be indicative of bone marrow involvement. This study included 60 patients with malignant lymphoma. Unilateral bone marrow biopsy of the posterior iliac crest was performed. MRI of lumbar spine was studied within 24 hours of bone marrow biopsy. 22 healthy controls were used for the detection of MRI objectivity during visual evaluation. In 83% of patients (50/60), biopsy and MRI results agreed completely. In two patients, histologic sections failed to show any evidence of bone marrow involvement despite abnormal MRI signals suggestive of involvement. In three patients, MRI was completely normal despite biopsy proven bone marrow infiltration. False negativity (3/60) and false positivity (2/60) rates were very low. Negative biopsy findings with positive or equivocal MRI results should not exclude bone marrow involvement and needs further evaluation with bilateral or guided biopsy. Thus, we conclude that MRI of bone marrow is a fairly sensitive, noninvasive modality and might be of potential value in detecting bone marrow infiltration in malignant lymphoid neoplasms which can be utilized as a useful adjunct to standard staging procedures.     

Cytogenetic and myelodysplastic alterations after autologous hemopoietic stem cell transplantation

Secondary myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML) are today considered a primary complication of autologous hematopoietic stem cell transplantation. In our Center, 83 autografted patients underwent bone marrow (BM) biopsy and cytogenetic analysis at fixed intervals. Twelve patients developed non-clonal cytogenetic abnormalities and 10 patients clonal abnormalities, five of whom (three - 7, one - 5 and one t(9;11)) developed secondary MDS/AML. MDS was also diagnosed in two patients with a normal karyotype. In brief, seven patients (three males, four females; median age 36 years) developed MDS/AML 12-48 months (median 14) after autografting. The FAB diagnosis was AML-M2 in one, chronic myelomonocytic leukemia in two and refractory anemia with excess of blasts in transformation in four cases. Two patients presented a BM biopsy picture of MDS with fibrosis; none of them experienced leukemic transformation. Four MDS patients died, three of leukemic transformation and one of BM insufficiency; the two remaining patients are still living and untransformed. Our data underline the leukemogenic role of previous treatments, even if it is not possible to exclude that underlying disease and/or conditioning therapy may be involved.     

RARS with fibrosis and del(20q) transformed into ALL

Transformation of myelodysplastic syndrome (MDS) into acute myelogenous leukemia occurs in approximately 30?% of cases, while progression into acute lymphoblastic leukemia (ALL) is rare. We report on a 67-year-old man with the diagnosis of MDS, subtype refractory anemia with ring sideroblasts (RARS), karyotype 20q-?, JAK-2 negative and grade III fibrosis on the bone marrow biopsy, who evolved into ALL 33?months after the diagnosis of MDS. RARS is one of the subtypes of MDS with most indolent course. Deletion of the long arm of chromosome 20 (20q-) is considered as good prognosis by the International Prognostic Scoring System, an important scoring system for predicting survival and evolution of MDS. Primary MDS with bone marrow fibrosis may represent a distinct clinicopathological and is supposed to have an unfavorable prognosis. The combined analysis of these features makes this rare report still more challenging and illustrates that biology of MDS is yet to be discovered.     

Importance of bone marrow cytogenetic evaluation before autologous bone marrow transplantation for Hodgkin's disease

Alkylating agents used either with or without radiation therapy have been associated with the development of myelodysplastic syndrome (MDS) and acute nonlymphoblastic leukemia (ANLL) after treatment of both malignant and nonmalignant disorders. This report describes seven patients with recurrent Hodgkin's disease (HD) evaluated for bone marrow transplantation (BMT) who developed chromosomal abnormalities, and emphasizes the importance of bone marrow cytogenetic studies before bone marrow harvest. Three patients with histologically normal bone marrow underwent autologous BMT and subsequently developed an MDS or ANLL. Four patients had the clonal abnormality detected before bone marrow harvest and did not proceed to BMT.     

In vitro growth modulation by L-ascorbic acid of colony-forming cells from bone marrow of patients with myelodysplastic syndromes.

In vitro colony growth was studied on bone marrow cells from 51 patients with myelodysplastic syndromes (MDS), using a cell culture method with the unique feature of daily feeding, in an effort to gain insight into the pathophysiology of MDS and to assess the clinical utility of this cell culture assay. The colony growth pattern of MDS marrow cells is remarkably similar to that of acute myeloid leukemia but quite dissimilar from that of normal marrow, in support of a common pathophysiological mechanism for these two disorders. In particular, L-ascorbic acid (LAA) enhanced colony growth in 30% and suppressed growth in 16% of cases, a finding also similar to that in acute myeloid leukemia, indicating a unique growth requirement which may be explored for therapeutic purposes. Further, these LAA effects have prognostic value, with LAA-sensitive (both LAA-enhanced and LAA-suppressed) cases displaying shorter survivals than LAA-insensitive cases (median survival of 5 months versus 18 months; P = 0.011). This prognostic value is independent of, and more powerful than, bone marrow blasts; the median survival was 18 months for less than 5% bone marrow blasts and 8 months for greater than 5% bone marrow blasts (P = 0.044). These two risk factors can be used together to identify patients with an extremely good or an extremely poor prognosis. This study establishes the clinical usefulness of the LAA effect in MDS as a prognostic factor and provides a new lead to explore in understanding differential biochemical/molecular events and, possibly, a new therapeutic approach to the management of MDS.     

骨髓异常的磁共振成像及其临床应用研究

目的：探讨磁共振成像（magnetic reconance imaging,MRI) 在评价骨髓病变中的作用。方法：定性定量分析78例正常人群、44例骨髓病变患者（15例白血病、13例非霍奇金氏淋巴瘤、16例增生性贫血）的脊柱MRI汲骨髓穿刺、外周血检查资料，并将MRI定量资料与临床实验室检查资料进行相关性分析。全部病例均经骨髓穿刺或活检证实。结果：①白血病及淋巴瘤T1加权像（T1-weigted imaging,T1WI)低信号多于增生性贫血及正常人群（P＜0．05），T2加权像（T2-weigted imaging,T2WI)高信号多于增生性贫血及正常人群（P＜0．05）；正常人群、白血病、淋巴瘤强化无差异（P＞0．05）；白血病弥漫性浸润多于淋巴瘤（P＝0．000）。②T1WI白血病及淋巴瘤骨髓肌肉信号强度比（signal intensity ratio on T1WI,SIR1)低于增生性贫血及正常人群（P＜0．05）。③增生性贫血SIR1与粒细胞和红细胞之比呈正相关（P＝0．006），与骨髓中红细胞比例负相关（P＝0．008）；白血病SIR1与骨髓幼稚细胞比例负相关（P＝0．048）。结论：MRI可显示脊柱红骨髓的分布；MRI定性分析可区分良、恶性骨髓病变；定量分析SIR1诊断价值有限；SIR1可评价增生性贫血的贫血程度，粗略预测白血病的瘤负荷。     

恶性血液病继发骨髓纤维化69例

目的探讨继发性骨髓纤维化（SMF）患者的临床及骨髓病理学特征。方法对69例SMF患者的临床表现、外周血涂片、骨髓涂片及骨髓活检情况进行回顾性分析,对不同疾病骨髓纤维化程度与巨核细胞数目进行相关性分析。结果69例SMF患者原发病分别为慢性粒细胞白血病（CML）20例（29．0％）,淋巴瘤14例（203％）,急性髓系白血病（AML）、骨髓增生异常综合征（MDS）各10例（14．5％）,急性淋巴细胞白血病（ALL）6例（8．7％）,多发性骨髓瘤（MM）4例（5．8％）,骨髓增殖性肿瘤（MPN）3例（4．3％）,慢性淋巴细胞白血病（CLL）2例（2．9％）。病理骨髓纤维化程度与巨核细胞数之间无相关性（r=0．024,P=0．848）。结论临床上多种血液系统疾病可以引起SMF。初诊的造血系统恶性疾病患者应同时行骨髓活检,特别是脾大、骨髓“干抽”的患者要考虑SMF的可能,骨髓病理学检查对临床诊断和鉴别诊断具有重要意义。     

骨髓涂片联合骨髓活检诊断骨髓增生异常综合征86例

 目的　探讨骨髓穿刺涂片与骨髓活检切片同步观察对诊断骨髓增生异常综合征（MDS）的临床意义。方法　对86例MDS患者采用骨髓抽吸-活检双标本一步法取材,同步观察其涂片和切片。结果　86例MDS患者骨髓穿刺涂片增生程度极度减低至减低30例（34.88 %）,活跃、明显活跃、极度活跃56例（65.12 %）,红系病态造血43例（50.00 %）,粒系病态造血32例（37.21 %）,巨核系病态造血22例（25.58 %）。骨髓活检切片的增生程度极度减低至减低15例（17.44 %）,活跃、明显活跃、极度活跃71例（82.56 %）;红系病态造血16例（18.61 %）,粒系病态造血52例（60.47 %）,巨核系病态造血56例（65.12 %）。86例中66例切片与涂片WHO分型诊断一致,符合率76.74 %。结论　骨髓涂片和活检在MDS的诊断和分型中各有优点,两者相互补充,二者同步观察更有利于提高MDS诊断和分型的准确性。     

Proliferation and apoptosis in acute and chronic leukemias and myelodysplastic syndrome

Clonal expansion of leukemic cells is thought to be due to proliferation in excess of apoptosis. To define and compare proliferation and apoptosis between various leukemias and myelodysplastic syndrome (MDS), we measured proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU) incorporation as surrogate markers for proliferation and caspase 3 activity and annexin V surface binding as surrogate markers for activation of the apoptotic cascade in patients with MDS, chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). We found high proliferation in bone marrow cells from MDS and CMML as measured by PCNA and BrdU incorporation. The lowest level of proliferation was found in CLL. Apoptosis was also highest in MDS and CMML as measured by annexin V and caspase 3 activity. Unexpectedly, we found no significant difference in proliferation in bone marrow CD34+ cells from various leukemias or MDS. Apoptosis was significantly higher in bone marrow CD34+ cells from MDS and CML in chronic phase as compared to CD34+ cells from AML patients. Our results illustrate differences in proliferation and apoptosis between acute and chronic leukemias and MDS. These differences may have diagnostic and therapeutic implications.     

Hypoplastic myelodysplastic syndrome

Over a period of 8 years 11 of 64 patients seen at Loyola University Medical Center with the diagnosis of myelodysplastic syndrome (MDS) also exhibited bone marrow hypoplasia (marrow cellularity of 25% or less) at presentation. The other 53 had normocellular or hypercellular marrow. Clinical features, hemograms, chromosome analysis, incidence of progression to acute leukemia or aplastic anemia, and survival in each group were compared. Using the French-American-British (FAB) classification, there were seven patients with refractory anemia (RA), one refractory anemia with ringed sideroblasts (RARS), and three refractory anemia with excess blasts (RAEB) in the hypoplastic MDS group. Those with normocellular or hypercellular marrow included 22 with RA, nine with RARS, 12 with RAEB, three with chronic myelomonocytic leukemia, and four with RAEB in transformation; one had chronic diGuglielmo syndrome and two patients were not classified. Patients with hypoplastic MDS had lower hemoglobin levels (median, 8 g/dl versus 9 g/dl), more severe leucopenia (median 3100/microliter versus 4200/microliter) and thrombocytopenia (median, 28,000/microliter versus 75,000/microliter), and marked macrocytosis (mean corpuscular volume (MCV), 107 mu 3 versus 97 mu 3). Nine patients with hypoplastic MDS had a chromosome analysis of the bone marrow, and all were normal. In those with normocellular or hyperplastic bone marrow, 22 such analyses were done, and seven (23%) were abnormal. One patient (11%) from the hypoplastic group and 11 (23%) from the normocellular or hyperplastic MDS transformed into acute leukemia. None progressed to aplastic anemia. With a mean follow-up time of 33 months in the hypoplastic MDS, eight patients (72%) are alive. In the group with normal or hyperplastic MDS, the mean follow up was 47 months, and 27 patients (50%) have survived. The two groups differ significantly in leukocyte count (P less than 0.0015), platelet count (P less than 0.0001), and MCV (P less than 0.0023). There may be a possible difference between these groups related to abnormal karyotype, but it is not statistically significant (P = 0.06). Therapy with pyridoxine, folic acid, prednisone, anabolic steroids, retinoids, or low-dose cytosine arabinoside was not beneficial in hypoplastic MDS. Hypoplastic MDS appears to be a distinct clinicopathologic entity characterized by marrow hypoplasia, macrocytosis, severe leucopenia and thrombocytopenia, low incidence of progression to acute leukemia, and unresponsiveness to conventional therapy.     

The prognostic significance of bone marrow levels of neurofibromatosis-1 protein and ras oncogene mutations in patients with acute myeloid leukemia and myelodysplastic syndrome

BACKGROUND: It has been reported that point mutations of the ras gene occur frequently in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the prognostic significance of ras gene mutations in patients with these disorders has been a controversial issue. Although abnormalities in the neurofibromatosis 1 (NF1) gene, which is a gene involved in the ras pathway, have been observed frequently in patients with juvenile chronic myelogenous leukemia, the role of these abnormalities in adult patients with AML or MDS is not clear. METHODS: In this study, bone marrow specimens that were obtained from previously untreated patients with AML and MDS were examined for ras mutations, and the levels of NF1 protein expression were measured. RESULTS: Ras point mutations were detected in 16 of 83 patients with AML (19%) and in 21 of 90 patients with MDS (23%). Fourteen of 28 patients with chronic myelomonocytic leukemia (50%) had ras gene mutations. Decreased bone marrow levels of NF1 protein (< 70% of the median level detected in control bone marrow specimens) were observed in 20 of 66 patients with AML (30.3%) and in 8 of 29 patients with MDS (27.6%); none of the patients with ras gene mutations had decreased bone marrow levels of NF1 protein. The presence of a mutant ras gene was associated with a shorter complete remission duration (CRD) in patients with MDS (P = 0.05) but had no effect on survival in patients with AML or MDS. Patients with AML who had decreased NF1 protein levels had a slightly longer CRD compared with patients who had normal NF1 levels (P = 0.07). However, the NF1 level had no significant impact on survival among patients with AML or MDS. When patients with low NF1 levels were grouped with patients who had ras mutations, the patients who had AML had a significantly longer CRD compared with the patients who had MDS (P = 0.02). CONCLUSIONS: The current results suggest that a reduction in NF1 protein expression and the presence of ras point mutations may complement each other and that they both play a complex role in the biology of AML and MDS.     

Diagnosis of myelodysplastic syndromes in cytopenic patients

Sustained clinical cytopenia is a frequent laboratory finding in ambulatory and hospitalized patients. For pathologists and hematopathologists who examine the bone marrow (BM), a diagnosis of cytopenia secondary to an infiltrative BM process or acute leukemia can be readily established based on morphologic evaluation and flow cytometry immunophenotyping. However, it can be more challenging to establish a diagnosis of myelodysplastic syndrome (MDS). In this article, the practical approaches for establishing or excluding a diagnosis of MDS (especially low-grade MDS) in patients with clinical cytopenia are discussed along with the current diagnostic recommendations provided by the World Health Organization and the International Working Group for MDS.     

Comprehensive scanning of somatic mitochondrial DNA alterations in acute leukemia developing from myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are clonal myeloid disorders characterized by ineffective hematopoiesis resulting in refractory cytopenias. Transformation resulting in acute myeloblastic leukemia is the final stage in the multistep process of MDS evolution. Functional relevant mutations of mitochondrial DNA (mtDNA) have been related to sideroblastic anemia and MDS. To investigate the role of mtDNA in malignant transformation to acute leukemia, we used high-resolution techniques such as single-strand conformational polymorphism and fluorescence sequencing for investigation of the whole mitochondrial genome from blood cells of 10 patients with MDS. Functionally relevant point mutations in mitochondrial RNA and polypeptide-encoding genes were detected in 50% of patients with MDS. Their increasing mutation load connects MDS and the developing acute myeloid leukemias. Several point mutations of mtDNA, including secondary point mutations for Leber's hereditary optic neuropathy, occur in one bone marrow and may synergically affect bone marrow stem cells by an apoptotic pathway.     

In myelodysplastic syndromes progression to leukemia is directly related to PHA dependency for colony formation and independent of in vitro maturation capacity

In an agar-liquid double-layer colony assay in which myeloid leukemia colony-forming cells require the presence of both the lectin PHA and CSF for in vitro proliferation, colony formation of bone marrow cells derived from patients with a myelodysplastic syndrome (MDS) was studied. In five of 14 MDS and all five leukemic transformed MDS cases, colony formation was found to require both PHA and CSF. Three of these five PHA-dependent MDS cases progressed to overt leukemia within 1 year, one progressed from RA to RAEB, and one patient received AML chemotherapy. PHA-dependent colony formation was associated with higher bone marrow blast counts, but not directly to FAB type or cytogenetic abnormalities. In nine other MDS cases only CSF was required for colony formation. In these PHA-independent cases the course of the disease was stable during the observation time (5-17 months). Two types of colonies were observed in this in vitro system: colonies adherent and colonies nonadherent to the agar underlayer. The former consisted of terminally differentiated myeloid cells, and the latter comprised immature cells. This suggests that the percentage of adherent colonies formed in vitro may be used as a measure for the maturation defect in MDS. However, no correlation was found between the percentage of adherent colonies and progression to leukemia of the MDS cases. Our findings suggest that the dependency on PHA for in vitro colony formation of colony-forming cells in MDS is predictive for the progression to leukemia. However, the in vitro differentiation capacity has no apparent prognostic significance.     

Standards and impact of hematopathology in myelodysplastic syndromes (MDS)

The diagnosis, classification, and prognostication of patients with myelodysplastic syndromes (MDS) are usually based on clinical parameters, analysis of peripheral blood and bone marrow smears, and cytogenetic determinants. However, a thorough histologic and immunohistochemical examination of the bone marrow is often required for a final diagnosis and exact classification in these patients. Notably, histology and immunohistology may reveal dysplasia in megakaryocytes or other bone marrow lineages and/or the presence of clusters of CD34-positive precursor cells. In other cases, histology may reveal an unrelated or co-existing hematopoietic neoplasm, or may support the conclusion the patient is suffering from acute myeloid leukemia rather than MDS. Moreover, histologic investigations and immunohistology may reveal an increase in tryptase-positive cells, a coexisting systemic mastocytosis, or bone marrow fibrosis, which is of prognostic significance. To discuss diagnostic algorithms, terminologies, parameters, and specific issues in the hematopathologic evaluation of MDS, a Working Conference involving a consortium of US and EU experts, was organized in June 2010. The outcomes of the conference and resulting recommendations provided by the faculty, are reported in this article. These guidelines should assist in the diagnosis, classification, and prognostication in MDS in daily practice as well as in clinical trials.     

Myelofibrosis in primary myelodysplastic syndromes

In a retrospective study of 236 patients with primary myelodysplastic syndromes (MDS), 130 cases (55.1%) revealed myelofibrosis in bone marrow biopsies. It was observed that fibrosis mostly occurs focally or patchy, and collagen deposits were found very rarely (only four patients). The histopathology of bone marrow biopsies revealed several differences between fibrotic and non-fibrotic MDS: cellularity is significantly higher, dysmegakaryopoiesis is more pronounced, plasmocytes and mast cells are more often increased, and disturbance of marrow topography (particularly of the MK- and G-line) can be found more frequently in MDS with myelofibrosis. Reticulin fibrosis occurred in all subtypes of MDS; however, there was a higher incidence in chronic myelomonocytic leukemia. The frequency of abnormal growth of GM-progenitors was significantly higher in the MDS cases with myelofibrosis, compared to the cases without fibrosis. Clinical data showed significantly higher WBC, more frequent presence of immature granulocytes, and higher percentage of myeloblasts in peripheral blood and bone marrow in MDS with myelofibrosis compared to cases without myelofibrosis. Life expectancy was reduced to 13 mo, compared with 35 mo in MDS without fibrosis (p=0.00055). Time to leukemic transformation was 32 mo in MDS with fibrosis, compared with >56 mo in MDS without fibrosis (p=0.015). Myelofibrosis therefore seems to herald a poor prognosis.     

Magnetic resonance imaging to detect bone marrow metastases in the initial staging of small cell lung carcinoma and breast carcinoma

BACKGROUND: Bone marrow is a common site of metastases in patients with small cell lung carcinoma (SCLC) and female breast carcinoma (FBC). Metastatic bone marrow involvement is found in approximately 50% of SCLC patients and up to 85% of FBC patients at autopsy. Initial staging procedures detect malignant bone marrow lesions in only 2-30% of patients with these tumors. This study was performed to assess whether MRI can improve the detection rate of bone marrow metastases in tumors with a high incidence of skeletal involvement. METHODS: Fifty-two patients with histologically verified SCLC (25 with limited stage disease and 27 with extensive stage disease) and 33 women with FBC were entered into a prospective study. The MRI protocol was comprised of coronal slices in the pelvic region and sagittal slices of the whole spine utilizing a T1-weighted spin echo sequence with a field of view of 50 cm. All patients underwent initial routine diagnostic staging procedures including bone scintigraphy, unilateral crest biopsy, and plain film radiography of suspicious skeletal areas. RESULTS: Only in two SCLC patients, MRI was positive in 25 cases. All SCLC patients with bone marrow lesions histologically verified, diagnosed by crest biopsy (six patients) or by bone scan (seven patients) had the correct diagnosis of metastases by MRI. In addition MRI revealed hypointense bone marrow foci in 14 cases. In contrast, 28 of 33 FBC patients examined during the initial staging procedure showed no evidence of bone marrow involvement. MRI was not superior compared with bone scintigraphy in FBC patients. CONCLUSIONS: The staging results obtained in SCLC and FBC patients are different, although both tumors have a high incidence of bone marrow metastases. It may be assumed that the biologic behavior of these tumors is reflected by the initial bone marrow involvement. Because of its superiority compared with biopsy and bone scan, the authors believe MRI should become an integral part of the initial staging procedures in patients with SCLC. When staging patients with FBC, MRI should be applied only in clinically indicated cases.     

Having a higher blast percentage in circulation than bone marrow: clinical implications in myelodysplastic syndrome and acute lymphoid and myeloid leukemias.

Determining the percentage of peripheral blood (PB) and bone marrow (BM) blasts is important for diagnosing and classifying acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Although most patients with acute leukemia or MDS have a higher percentage of BM blasts than PB blasts, the relative proportion is reversed in some patients. We explored the clinical relevance of this phenomenon in MDS (n = 446), AML (n = 1314), and acute lymphoblastic leukemia (ALL) (n = 385). Among patients with MDS or ALL, but not AML, having a higher blast percentage in PB than in BM was associated with significantly shorter survival. In multivariate analyses, these associations were independent of other relevant predictors, including cytogenetic status. Our findings suggest that MDS and ALL patients who have a higher percentage of PB blasts than BM blasts have more aggressive disease. These data also suggest that MDS classification schemes should take into account the percentage of blasts in PB differently from the percentage of blasts in BM.     

Expression of IAP family proteins in myelodysplastic syndromes transforming to overt leukemia

Bone marrow cells of patients with myelodysplastic syndromes (MDS) frequently undergo apoptosis, though the apoptotic cell ratio decreases when overt leukemia (OL) develops. Thus, we compared the expression of the inhibitor of apoptosis protein (IAP) gene family proteins in bone marrow samples from control, MDS, OL transformed from MDS (MDS --> OL), and de novo acute myelogenous leukemia (AML) subjects by the quantitative real-time RT-PCR method and an immunohistochemical approach. Overexpression of mRNA for survivin, cIAP1, NAIP and XIAP was significant in MDS bone marrow cells compared with control samples. However, the expression of mRNA for survivin, cIAP1 and cIAP2 exhibited a remarkable decrease after the development of OL (MDS --> OL). By immunohistochemistry, survivin was found to localize to the nucleus of myeloid cells in the majority of MDS cases. Next, the chronological changes in the expression of IAPs were determined in cases of MDS with evolution of OL. Although the expression of cIAP1 and cIAP2 revealed a sudden or gradual decrease as OL developed, survivin in many cases and XIAP in the majority of cases exhibited a peak of expression before a decline, indicating that these IAPs could be associated with the early events in the development of OL.