A focused review of hematopoietic neoplasms occurring in the therapy-related setting

Hematological neoplasms developed in patients with a history of cytotoxic therapies comprise a group of diseases with a poor clinical outcome, and collectively categorized as “therapy-related myeloid neoplasms” (t-MN) in the 2008 World Health Organization (WHO) Classification. In recent years, numerous publications have emerged, and these studies have greatly expanded the scope of our understanding in this field. We here focused our review on several selected areas including secondary malignancies occurring in patients with autoimmune diseases; radiation therapy alone as a causative agent; the similarity and differences between therapy-related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML); clinical behavior and treatment outcome of t-AML patients with favorable cytogenetics; the incidence and clinical features of myelodysplastic/myeloproliferative neoplasms, as well as acute lymphoblastic leukemia and myeloproliferative neoplasms in patients with prior cytotoxic exposure. These recent studies have shown that therapy-related hematopoietic neoplasms are heterogeneous, and may manifest in various forms, more complex than we have recognized previously. Cytogenetic abnormalities and underlying mutations are likely to be the major factors dictating prognosis.     

From cellular morphology to molecular and epigenetic anomalies of myelodysplastic syndromes

Myelodysplastic syndromes (MDSs) are a myeloid neoplasm with a propensity for natural evolution or transformation to acute leukemias (AL) over time. Mechanisms for MDS transformation to AL remain poorly understood but are related to genomic instability, which affects the production of the different cell lineages. Genomic instability is also generated by dysfunctional telomeres. Indeed telomeres, the protective ends of chromosomes are the backbone of genome stability. Nuclear telomere remodeling is an early indicator of nuclear remodeling preceding the onset of genomic instability and MDS. This review aims to revisit the pathogenesis and pathophysiology of MDS from morphology and cytogenetics to molecular and epigenetic mechanisms. Furthermore, this review will highlight and discuss recent breakthroughs in dysfunctional telomeres and nuclear telomere architecture roles in the pathogenesis and physiopathology of MDS in the global context of genomic instability.     

The presence of a chromosomal abnormality in cytopenia without dysplasia identifies a category of high-risk clonal cytopenia of unknown significance

Myelodysplastic syndromes (MDS) are hematological malignancies classically defined by the presence of cytopenia(s) and dysmorphic myeloid cells. It is now known that MDS can be preceded by a pre-malignant condition called clonal cytopenia of unknown significance (CCUS), which associates a clonality marker with cytopenia in the absence of criteria of dysplasia. However, to date, it is not clear whether chromosomal abnormalities should be considered in the definition of CCUS or if they carry a prognostic impact in CCUS patients. In this study, we analyzed the clinico-biological features and outcomes of 34 patients who presented with one or more cytopenias, an absence of significant dysplasia, and a presence of a chromosomal abnormality (CA). We named this entity chromosomal abnormality with cytopenia of undetermined significance (CACtUS). We show that these patients are slightly older than MDS patients and that they more frequently presented with normocytic anemia. Most CACtUS patients exhibited only one unbalanced CA. The number and type of mutations were comparable between CACtUS patients and MDS patients. Regardless of the cytogenetic abnormality, the clinicobiological characteristics, overall survival, and risk of progression to high-risk (HR) MDS were similar between CACtUS patients and low-risk MDS patients. Thus, we suggest that CACtUS patients can be considered as HR-CCUS and should receive the follow-up regimen recommended for MDS patients.     

HLA-A*02:06 allele may be susceptible to myelodysplastic syndrome in Zhejiang Han population,China

The association between HLA loci and haematological malignancy has been reported in certain populations. However, there are limited data for HLA loci at a high-resolution level with haematological malignancy in China. In this study, a total of 1115 patients with haematological malignancies (including 490 AML, 410 acute lymphoblastic leukaemia (ALL), 122 myelodysplastic syndrome [MDS] and 93 non-Hodgkin's lymphoma [NHL]) and 1836 healthy individuals as a control group in the Han population of Zhejiang Province, China, were genotyped for HLA-A, HLA-C, HLA-B, HLA-DRB1 and HLA-DQB1 loci at high resolution. The possible association between HLA alleles and haplotypes and haematologic malignancy was analysed. The allele frequencies (AFs) of HLA-A*02:05, HLA-A*02:06, HLA-A*32:01, HLA-B*35:03, HLA-B*54:01, HLA-B*55:07, HLA-DRB1*04:05, HLA-DRB1*15:01, HLA-DQB1*04:01 and HLA-DQB1*06:02 in the MDS patients were much higher than those in the control group (P < 0.05), while the AFs of HLA-C*07:02, HLA-DRB1*03:01, HLA-DRB1*14:54, HLA-DQB1*02:01 and HLA-DQB1*05:03 were obviously lower than those in the control group (p < .05). Interestingly, the differences in these HLA alleles in patients with MDS were not significant after applying Bonferroni correction (Pc > .05), except for HLA-A*02:06 (Pc < .01). There were 13, 6 and 10 HLA alleles with uncorrected significant differences (p < .05) among patients with AML, ALL and NHL, respectively, compared with those in the control group, but the differences in these HLA alleles were not significant after correction (Pc > .05). Compared to those of the control group, there were some haplotypes over 1.00% frequency in patients with AML, MDS and NHL patients with uncorrected significant differences (p < .05). However, none of them showed a significant difference after correction as well (Pc > .05). The study reveals that HLA-A*02:06 may lead to susceptibility to MDS, but none of the HLA alleles were associated with AML, ALL or NHL after correction. These data will help to further understand the role of HLA loci in the pathogenesis of haematological malignancy in China.     

Incidence of apoptosis in HIV-myelopathy, myelodysplastic syndromes and non-specific inflammatory lesions of the bone marrow

Myelodysplastic syndromes, AIDS-related myelopathy and non-specific inflammatory reactions (mostly rheumatoid myelitis) are characterized by normo- to hypercellular bone marrow, but frequently display cytopenias in the peripheral blood. In the current study we have addressed the question whether this situation reflects an increased programmed cell death in haemopoiesis. For this purpose, the in situ end-labelling technique was applied to formalin-fixed and paraffin-embedded trephine biopsies derived from patients and a control group without any haematological disorder. Results were evaluated by morphometry. Significantly more apoptotic cell death was observed in the haemopoietic marrow of patients with either disease. Using double-immunohistochemistry with the monoclonal antibody PG-M1 (CD68), we were able to demonstrate that approximately one third of the apoptotic cells were ingested by macrophages. Our findings are in keeping with previously published data that postulated increased frequencies of macrophages in these disorders as well as raised serum levels of TNF-α.     

Histological and cytogenetic characterization of bone marrow in relation to prognosis and diagnosis of myelodysplastic syndromes

Bone marrow (BM) histology of 102 myelodysplastic syndromes (MDS) patients was analyzed retrospectively. All the cases were reclassified according to the World Health Organization (WHO) classification. Karyotype study was conducted for all except one. Fifteen of the MDS cases were hypoplastic. The cellularity in bone marrow histology is sometimes ineffective in the differential diagnosis of MDS and aplastic anemia (AA). Nonetheless, a marked decrease in the number of megakaryocytes (average, 0.3/mm(2); range, 0-2/mm(2)) even in the hyperplastic foci of the marrow of AA was the most important histological feature differentiating AA from MDS, whereas the number of megakaryocytes increased in most MDS cases (44/mm(2); range, 1-240/mm(2)) and also in hypoplastic MDS (14/mm(2); range, 8-26/mm(2)). Hyperplastic marrow had a significantly high frequency of progress to acute myeloid leukemia (AML) and hypoplastic MDS had a lower rate of progress to AML. Severe myelofibrosis had a significantly poor prognosis. An increase in CD34-positive cells in MDS indicated a high rate of progress to AML. As for the patients with refractory cytopenia with multilineage dysplasia (RCMD; the new category under the WHO classification), the increased number of megakaryocytes was correlated with poor prognosis.     

Effects of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor on respiratory burst activity of neutrophiis in patients with myelodysplastic syndromes

The superoxide (O₂-releasing capacity in response lo N-fomiyl-methionyl-leucyl-phenylalanine (FMLP)and the priming effects ofrecombinant human granuloeyte colony-stimulating factor (rhG-CSF) and granulocyte-macrophage colony-stimulating faclor (rhGM-CSF) on FMLP-induced O₂ release were investigated in neutrophils from 14 patients with myelodysplastic syndromes (MDS). The O₂ -releasing capacity in MDS neutrophils varied from patient to patient. As compared with normal neutJ-ophils. theO₂-releasing capacity in MDS neutrophils was increased in 9/14 patients, nonnal in three patients and decreased in two patients. There was no close relationship between the 02-reIeasing capacity and the peripheral blood neutrophil count or the plasma concentration of C-reactive protein. The priming of neutrophils by rhG-CSF was not observed in five patients, whereas rhGM-CSF primed neutrophils from all patients. The priming eflect of rhGM-CSF was consistently greater than that of rhG-CSF in each patient. The intravenous administration of rhG-CSF (300 μg/body) to two MDS patients showed an increase in the peripheral blood neutrophil count and enhancement of neutrophil O₂ release. These findings demonstrate that the neutrophil O₂-releasing capacity in MDS varies from patient to patient and is not always impaired, and that rhGM-CSF is able to prime neutrophils which never respond to rhG-CSF.     

Cryptic aberrations may allow more accurate prognostic classification of patients with myelodysplastic syndromes and clonal evolution

The karyotype of bone‐marrow cells at the time of diagnosis is one of the most important prognostic factors in patients with myelodysplastic syndromes (MDS). In some cases, the acquisition of additional genetic aberrations (clonal evolution [CE]) associated with clinical progression may occur during the disease. We analyzed a cohort of 469 MDS patients using a combination of molecular cytogenomic methods to identify cryptic aberrations and to assess their potential role in CE. We confirmed CE in 36 (8%) patients. The analysis of bone‐marrow samples with a combination of cytogenomic methods at diagnosis and after CE identified 214 chromosomal aberrations. The early genetic changes in the diagnostic samples were frequently MDS specific (17 MDS‐specific/57 early changes). Most progression‐related aberrations identified after CE were not MDS specific (131 non‐MDS‐specific/155 progression‐related changes). Copy number neutral loss of heterozygosity (CN‐LOH) was detected in 19% of patients. MDS‐specific CN‐LOH (4q, 17p) was identified in three patients, and probably pathogenic homozygous mutations were found in TET2 (4q24) and TP53 (17p13.1) genes. We observed a statistically significant difference in overall survival (OS) between the groups of patients divided according to their diagnostic cytogenomic findings, with worse OS in the group with complex karyotypes (P = .021). A combination of cytogenomic methods allowed us to detect many cryptic genomic changes and identify genes and genomic regions that may represent therapeutic targets in patients with progressive MDS.     

多重荧光原位杂交结合染色体涂抹技术检测骨髓增生异常综合征复杂核型异常

目的探讨多重荧光原位杂交(multiplex fluorescence in situ hybridization,M-FISH)及全染色体涂抹(whole chromosome painting,WCP)技术在骨髓增生异常综合征(myelodysplastic syndromes,MDS)复杂核型异常检测中的价值。方法对7例常规R显带具有复杂染色体异常的MDS患者应用M-FISH技术确定复杂染色体的重排及标记染色体的组成,识别微小易位。并进一步采用双色WCP技术验证M-FISH检测的结果。结果M-FISH不仅证实了R显带的结果,而且确定了R带核型分析没有确定的6种标记染色体、9种有不明来源的额外物质增加的染色体、5种衍生染色体的组成和来源及4种被忽略的微小易位。涉及17号染色体的异常及-5/5q-是MDS最为常见的两种染色体异常。WCP技术纠正了一些M-FISH漏检及误检的异常。结论M-FISH是明确复杂染色体异常的很有用的分子生物学工具,WCP是M-FISH技术的重要补充,R带核型分析结合分子细胞遗传学工具M-FISH和WCP可以更加准确地描述复杂染色体异常。     

骨髓增生异常综合征巨噬细胞增生与造血细胞凋亡的相关性

目的 观察骨髓增生异常综合征(MDS)巨噬细胞增生状况与原位细胞凋亡的相关性并探讨其意义。方法 用碱性磷酸酶-抗碱性磷酸酶免疫酶标(APAAP)技术(CD68抗原标记)结合DNA末端原位标记(ISEL)分析30例MDS患者(其中低危组21例、高危组9例)骨髓塑料冷包埋切片中巨噬细胞数量和造血细胞原位凋亡状况,并分析二者间的相关性。缺铁性贫血(IDA)12例作对照。结果 (1)MDS患者骨髓切片中CD68阳性细胞数为(29.2±33.0)/mm~2,对照组为(21.2±16.7)/mm~2(P>0.05);(2)MDS病例凋亡细胞数平均为(71.5±70.9)/mm~2,对照组为(37.3±23.0)/mm~2(P<0.05);(3)MDS低危组CD68阳性细胞[(35.5±37.0)/mm~2]和凋亡细胞数[(90.7±74.6)/mm~2]均高于高危组[(14.6±11.7)/mm~2和(26.8±33.1)/mm~2](P分别<0.05和<0.01);(4)MDS病例CD68阳性细胞数与造血细胞凋亡显示显著正相关;r=0.83,P<0.001;(5)MDS病例骨髓切片中CD68阳性细胞与凋亡细胞不显示位置上的相关性;(6)MDS病例CD68阳性细胞本身存在过度凋亡。结论 MDS存在过度凋亡;MDS低危组凋亡高于高危组;MDS巨噬细胞与造血细胞凋亡具有相关性。     

Precursors of acute leukemia: myelodysplastic syndromes and myeloproliferative neoplasms

Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) represent neoplastic proliferations of hematopoietic stem cells, which may progress to loss of differentiation and acute myeloid leukemia (AML). Transitions between MDSs and MPNs as well as combinations between both disorders occur and MPNs may acquire dysplastic features combined with cytopenia. Myelodysplastic/myeloproliferative neoplasms show dysplastic and myeloproliferative properties and have in common genetic aberrations at the stem cell level (TET2, ASXL?1, CBL, IDH?1, IDH?2, EZH2, p53, Runx1), which may be found in one cell or may affect different hematopoietic stem cells, expanding in parallel. Progress to AML follows a linear clonal evolution only in a subset of cases. Alternatively AML derives from secondary clones, devoid of any marker mutation or originates from a common aberrant progenitor cell which shares other but not the JAK2 ( V617F ) mutation.     

骨髓增生异常/骨髓增殖性肿瘤1例诊治分析

了解骨髓增生异常/骨髓增殖性肿瘤(myelodysplastic/myeloproliferative neoplasms,MDS/MPN)的临床类型、病理特征、基因突变,对其预后进行评估.收集1例MDS/MPN病例及相关参考文献,观察其临床表现、临床病理学特征、基因突变及最终临床分型,判断治疗疗效,并进行预后评价.MDS/MPN同时具有MDS和MPN的临床及主要血液学特点,目前分为慢性粒单细胞白血病、不典型慢性粒细胞白血病,BCR-ABL1阴性(atypical chronic myeloid leukemia,aCML)、幼年型粒单细胞白血病(juvenile myelomonocytic leukemia,JMML)、伴环形铁粒幼细胞和血小板增多的骨髓增生异常/骨髓增殖性肿瘤(MDS/MPN with ring sideroblasts and thrombocytosis,MDS/MPN-RS-T)、MDS/MPN,无法分类(MDS/MPN-unclassifiable,MDS/MPN-U)等5种类型.各型有其不同诊断标准,而上述不同疾病之间出现转化,国内未见报道.保定市第一医院诊治1例最初诊断不明确的慢性髓系恶性肿瘤,随着疾病的演变而最终确诊为慢性粒单细胞白血病.通过本病例表明,在不同类型MDS/MPN之间可能会存在类型转换.     

Genetics of skin appendage neoplasms and related syndromes

In the past decade the molecular basis of many inherited syndromes has been unravelled. This article reviews the clinical and genetic aspects of inherited syndromes that are characterised by skin appendage neoplasms, including Cowden syndrome, Birt-Hogg-Dube syndrome, naevoid basal cell carcinoma syndrome, generalised basaloid follicular hamartoma syndrome, Bazex syndrome, Brooke-Spiegler syndrome, familial cylindromatosis, multiple familial trichoepitheliomas, and Muir-Torre syndrome.