Pathophysiological Scenario of Hematopoietic Disorders: A Comparative Study of Aplastic Anemia,Myelodysplastic Syndrome and Leukemia in Experimental Animals

The conversion of physiology to pathophysiology in hematological disorders viz: aplastic anemia, myelodysplastic syndrome (MDS) and leukemia in murine models was the subject of study in the present programme. Peripheral blood hemogram, spleno-somatic index, bone marrow smear study, cytochemical staining of marrow, cell release kinetics study during marrow explants culture, hematopoietic niche assessment, chromosomal aberration study, plasma membrane stability study of marrow cells, lysosomal membrane and mitochondrial membrane stability study and innate immune parameters were performed in the aplastic anemia, leukemia and MDS mouse model. In bone marrow aplasia, peripheral blood pancytopenia, marrow hypocellularity, decreased marrow cellular viability, deterioration of bone marrow hematopoiesis as well as hematopoietic microenvironment and extramedullary hematopoiesis were noticed. In addition, disruption of mitochondrial and lysosomal membrane integrity along with reduction of innate immune parameters were found in the hematopoietic suppressed condition. Surprisingly, no noticeable chromosomal aberration was found in the aplastic condition. Ineffective marrow hematopoiesis together with the disruption of hematopoietic microenvironment was observed in MDS. Also, extramedullary hematopoiesis, increased marrow cellular death, chromosomal aberration and loss of innate immunity were the common events. During leukemia, the number of functionally and structurally immature cells in the peripheral blood and bone marrow was increased together with malignant conversion of hematopoietic cells in the presence of malignancy supportive stromal microenvironment. Chromosomal aberration, decrease of cell mediated immunity with least mitochondrial apoptotic damage were also found in leukemic condition as well.     

Refractory cytopenias: clinical course according to bone marrow cytology and cellularity

One hundred and one patients with refractory cytopenia were reviewed for morphological classification (using bone marrow, BM, imprints for cytology and Jamshidi biopsies for BM cellularity) and clinical course. Final diagnoses were: moderate aplastic anemia (MAA), myelodysplastic syndromes (MDS) and hypoplastic acute leukemia (HAL). Ninety-two patients received high dose testosterone enanthate (TE) as first treatment (starting dose = 7-10 mg/week i.m. for at least three months). Median survival was significantly longer in MAA than in MDS and in HAL. Among MDS patients, those with primary acquired sideroblastic (AISA) and refractory (RA) anemia had median survival similar to those with MAA, but distinctly longer (p = 0.01) than patients with RA with an excess of blasts (RAEB), RAEB in transformation (RAEBtr) and chronic myelomonocytic leukemia (CMMoL). Acute leukemia (AL) developed more rarely (p less than 0.02) in MAA, AISA and RA than in RAEB, RAEBtr and CMMoL. Response to TE was seen in about two thirds of MAA and in a half of MDS and HAL patients. Among MDS patients, those with hypocellular BM developed leukemia less frequently, responded to androgens more often and survived longer than those with normocellular and, especially, with hypercellular BM. These data indicate that the cytohistological classification of refractory cytopenias identifies essentially two groups with different clinical behaviour, one (MAA, AISA and RA) having long life expectancy and a low probability of developing AL and the other (RAEB, RAEBtr, CMMoL) with a short survival and relatively frequent leukemic complication. Bone marrow hypocellularity seems to be a favourable prognostic factor in MDS. Patients with refractory cytopenias, especially those with a hypocellular BM, can be advantageously treated with androgens.     

Apoptotic rate in patients with myelodisplastic syndrome treated with modulatory compounds of pro-apoptotic cytokines

Excessive apoptosis has a central role in ineffective hematopoiesis in myelodysplastic syndrome (MDS). The aim of the study was to quantify apoptosis and Bcl-2 expression in patients with MDS and to use these parameters in the evaluation of treatment efficacy with compounds modulating proapoptotic cytokines. Bone marrow (BM) samples from eight MDS patients were studied: four with refractory anemia and four with refractory anemia with ringed sideroblasts. Two patients with Hodgkin disease without BM determination were studied for control. Therapy consisted in administration of pentoxyphylline, dexamethasone and ciprofloxacin. Biochemical assay of apoptosis and Bcl-2 was performed using annexin V-biotin conjugate antibody and anti-human Bcl-2 antibody respectively, followed by streptavidine-peroxidase conjugate, and peroxidase substrate. Ultrastructural investigation of BM samples was performed with standard electron microscopy techniques. Most of BM hematopoietic cells in the MDS patients had ultrastructural features of various stages of apoptosis including chromatin condensation and margination, cytoplasm condensation and budding of nuclear and plasma membranes to produce apoptotic bodies. Bcl-2 expression showed an inverse correlation with the rate of the apoptotic process. Periodic evaluation of these two parameters has shown an increase of Bcl-2 expression and a decrease of apoptotic rate in patients who had responded to the treatment. Response to the treatment was appreciated in accordance with their transfusion needs. Treatment efficiency diminished in time. The rate of apoptosis was inversely correlated with the level of Bcl-2 expression. These results confirm the importance of the apoptotic process evaluation in monitoring MDS treatment.     

Flow cytometric evaluation of proliferative activity and ploidy in myelodysplastic syndromes and acute leukemias

Propidium iodide (PI) DNA distribution of bone marrow (BM) cells was studied by flow cytometry (FCM) in 36 patients without hematologic or malignant disease (normal BM) and in 172 patients with anemias (36 pts), myelodysplastic syndromes (MDS) (33 pts) and acute leukemia (AL) at diagnosis (60 pts), remission (24 pts) and relapse (19 pts). White blood cells from normal male subjects were used as an external diploid reference standard (median CV = 3.8). Patients with normal BM, anemias, MDS and acute leukemia at diagnosis had tritiated thymidine labeling index (LI) and most with MDS and AL had also evaluable cytogenetics performed on the same BM sample used for FCM. In normal BM, median aliquot of cells with PI-DNA content intermediate between the diploid and the tetraploid value (2n-4n cells %) was 15.7. The ratio between the fluorescence intensity of the G0/1 peak of normal BM cells and the fluorescence intensity of the G0/1 peak of the reference standard (FI ratio) ranged from 93 to 1.05 (mean +/- 2SD). The 2n-4n cell % was higher than normal in anemias (p less than .001), lower in leukemias (p less than .001) and widely scattered in MDS. A linear correlation was found between 2n-4n cell % and LI, with 2n-4n cell % value higher than LI. The FI ratio was lower than normal in anemias (p less than .05), higher in AL with normal cytogenetics (p less than .02) and broadly scattered in MDS with normal cytogenetics. From our experience, PI-DNA-FCM is a simple and adequate method to evaluate proliferative activity in hematologic diseases. Nevertheless, caution must be taken in attributing small changes in FI ratio to aneuploidy, since they are found in anemias and in MDS and AL with normal cytogenetics, possibly due to differences in PI uptake by different cell types.     

The peculiarities of cytogenetic changes in different types of myelodysplastic syndrome

A cytogenetic study of bone marrow aspirate from 32 patients with different types of myelodysplastic syndrome (MDS) has been carried out. The patients were from eight regions of Ukraine. Chromosome deletions prevailed in the spectrum of karyotype changes. The largest number of chromosome abnormalities was revealed in patients with a refractory anemia with an excess of blasts (66.6% of cases). Chromosomal changes that involved three or more chromosomes occurred among 27% of all karyotype changes examined by us. Transformation of myelodysplastic syndrome to acute myeloid leukemia (AML) was found in 5 patients (45.4% of the cases) among 11 patients with abnormal karyotypes. We propose that cytogenetic confirmation of increased apoptosis in the bone marrow from the myelodysplastic syndrome patients is a phenomenon of chromosome fragmentation. The risk of transformation of myelodysplastic syndrome to acute myeloid leukemia was measured with the use of a new international score system, IPSS.     

Arsenic trioxide and ascorbic acid interfere with the BCL2 family genes in patients with myelodysplastic syndromes: an ex-vivo study

ABSTRACT: BACKGROUND: Arsenic Trioxide (ATO) is effective in about 20% of patients with myelodysplasia (MDS); its mechanisms of action have already been evaluated in vitro, but the in vivo activity is still not fully understood. Since ATO induces apoptosis in in vitro models, we compared the expression of 93 apoptotic genes in patients' bone marrow before and after ATO treatment. For this analysis, we selected 12 patients affected by MDS who received ATO in combination with Ascorbic Acid in the context of the Italian clinical trial NCT00803530, EudracT Number 2005-001321-28. METHODS: Real-time PCR quantitative assays for genes involved in apoptosis were performed using TaqMan(R) Assays in 384-Well Microfluidic Cards "TaqMan(R) Human Apoptosis Array". Quantitative RT-PCR for expression of EVI1 and WT1 genes was also performed. Gene expression values (Ct) were normalized to the median expression of 3 housekeeping genes present in the card (18S, ACTB and GAPDH). RESULTS: ATO treatment induced up-regulation of some pro-apoptotic genes, such as HRK, BAK1, CASPASE-5, BAD, TNFRSF1A, and BCL2L14 and down-regulation of ICEBERG. In the majority of cases with stable disease, apoptotic gene expression profile did not change, whereas in cases with advanced MDS more frequently pro-apoptotic genes were upregulated. Two patients achieved a major response: in the patient with refractory anemia the treatment down-regulated 69% of the pro-apoptotic genes, whereas 91% of the pro-apoptotic genes were up-regulated in the patient affected by refractory anemia with excess of blasts-1. Responsive patients showed a higher induction of BAD than those with stable disease. Finally, WT1 gene expression was down-regulated by the treatment in responsive cases. CONCLUSIONS: These results represent the basis for a possible association of ATO with other biological compounds able to modify the apoptotic pathways, such as inhibitors of the BCL2 family.     

Clonal monosomy of chromosome 21 in a case of myelodysplastic syndrome

This study reports on a cytogenetic finding in a bone marrow examination of a 47-year-old male patient treated in the Hematology and Blood Transfusion Service of the Hospital de Base in S?o José do Rio Preto, S?o Paulo State, Brazil. The only alteration found at diagnosis of myelodysplastic syndrome (MDS) subtype refractory anemia with excess blasts (RAEB-2) was clonal monosomy of chromosome 21. The patient evolved to acute myeloid leukemia type M2 and died nine months after diagnosis. Clonal monosomy of chromosome 21, as the only cytogenetic abnormality in MDS, has only been reported three times previously. This uncommon cytogenetic abnormality in MDS has been associated with a poor clinical course, although more data will be needed to determine if this prognosis is invariable.     

积分系统参与MDS诊断的可行性研究

目的:骨髓增生异常综合征(MDS)是一种起源于造血干细胞,以高风险向急性髓系白血病转化为特点的难治性血细胞质、量异常的异质性疾病。对不明原因血细胞减少或者有巨幼红细胞血症的老年人,如果得不到明确的诊断就不会获得有效的治疗。探讨对伴有不明原因血细胞减少或大红细胞血症患者采用一种积分系统来预测诊断为骨髓增生异常综合征(MDS)的可行性。方法:应用四个因子即年龄≥65,红细胞平均体积(MCV),红细胞分布宽度(RDW),和乳酸脱氢酶(LDH)的一个积分系统来计算诊断MDS的概率。结果:调查了303个病人,他们都因为不明原因的血细胞减少或者大红细胞血症在过去三年(2010~2012)进行了骨髓检查,最终三分之二患者被诊断为MDS,9%为疑似MDS,采用积分系统前后的MDS诊断率分别为12%和48%。结论:此四个因子的积分系统可以用于指导MDS患者的诊断。提高MDS的诊断率,减少不必要的骨髓穿刺,减轻病人的疼痛和医疗费用。     

Bone marrow macrophages are involved in the ineffective hematopoiesis of myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal disorders characterized by ineffective hematopoiesis. Accumulating evidence has shown that macrophages (MΦs) are important components in the regulation of tumor progression and hematopoietic stem cells (HSCs). However, the roles of bone marrow (BM) MΦs in regulating normal and malignant hematopoiesis in different clinical stages of MDS are largely unknown. Age-paired patients with lower-risk MDS (N = 15), higher-risk MDS (N = 15), de novo acute myeloid leukemia (AML) (N = 15), and healthy donors (HDs) (N = 15) were enrolled. Flow cytometry analysis showed increased pro-inflammatory monocyte subsets and a decreased classically activated (M1) MΦs/alternatively activated (M2) MΦs ratio in the BM of patients with higher-risk MDS compared to lower-risk MDS. BM MФs from patients with higher-risk MDS and AML showed impaired phagocytosis activity but increased migration compared with lower-risk MDS group. AML BM MΦs showed markedly higher S100A8/A9 levels than lower-risk MDS BM MΦs. More importantly, coculture experiments suggested that the HSC supporting abilities of BM MΦs from patients with higher-risk MDS decreased, whereas the malignant cell supporting abilities increased compared with lower-risk MDS. Gene Ontology enrichment comparing BM MΦs from lower-risk MDS and higher-risk MDS for genes was involved in hematopoiesis- and immunity-related pathways. Our results suggest that BM MΦs are involved in ineffective hematopoiesis in patients with MDS, which indicates that repairing aberrant BM MΦs may represent a promising therapeutic approach for patients with MDS.     

SNP array karyotyping allows for the detection of uniparental disomy and cryptic chromosomal abnormalities in MDS/MPD-U and MPD

We applied single nucleotide polymorphism arrays (SNP-A) to study karyotypic abnormalities in patients with atypical myeloproliferative syndromes (MPD), including myeloproliferative/myelodysplastic syndrome overlap both positive and negative for the JAK2 V617F mutation and secondary acute myeloid leukemia (AML). In typical MPD cases (N = 8), which served as a control group, those with a homozygous V617F mutation showed clear uniparental disomy (UPD) of 9p using SNP-A. Consistent with possible genomic instability, in 19/30 MDS/MPD-U patients, we found additional lesions not identified by metaphase cytogenetics. In addition to UPD9p, we also have detected UPD affecting other chromosomes, including 1 (2/30), 11 (4/30), 12 (1/30) and 22 (1/30). Transformation to AML was observed in 8/30 patients. In 5 V617F+ patients who progressed to AML, we show that SNP-A can allow for the detection of two modes of transformation: leukemic blasts evolving from either a wild-type jak2 precursor carrying other acquired chromosomal defects, or from a V617F+ mutant progenitor characterized by UPD9p. SNP-A-based detection of cryptic lesions in MDS/MPD-U may help explain the clinical heterogeneity of this disorder.     

Chromosome 11 rearrangements in various hematological neoplasias

Chromosome 11 abnormalities in leukemic bone marrow cells were observed in 14.0% of the cases of acute lymphoblastic leukemia (ALL), in 18.7% of acute myeloid leukemia (AML) cases, and in 16.7% of refractory anemia (RA) cases. Bands 11pl3, 11pl4, 11pl5 on the short arm and 11ql4, 11q21, 11q23 on the long arm of chromosome 11 were involved in these rearrangements. Rearrangements of band 11q23 were detected most often. Reciprocal translocations were found with the highest frequency, while para-and pericentic inversions and deletions, both terminal and interstitial, occurred less often. In RA cases only deletions were observed. Comparison of clinical features showed no correlation with age and major hematological indexes such as the number of blast cells in the initial period. These results show that the prognosis is poor in cases of abnormalities at both 11q21 and 11q23 in acute leukemia (AL) as well as in 11pl3 and 11pl5 in AML. This is the first observation of these phenomena.     

Conversion of polycythemia vera to refractory anemia with hyperplastic bone marrow.

Clinical and morphologic findings in the conversion of treated polycythemia vera to pancytopenia with hyperplastic bone marrow (refractory anemia or pancytopenia with hyperplastic bone marrow) are described in light of our own observation. The nomenclature associated with this condition (pancytopenia, chronic erythroleukemia, preleukemia) is not uniform, whereas the morphologic findings are virtually identical. Some patients subsequently develop acute leukemia. The prognosis in cases of refractory anemia with hyperplastic bone marrow following polycythemia vera is, independent of the subsequent acute leukemia, invariably terminal.     

Correlations between cytogenetics and morphology in myelodysplastic syndromes

In order to detect possible relationships between cytogenetic abnormalities and morphologic features in myelodysplastic syndromes (MDS), 48 patients with MDS were investigated. Clonal cytogenetic abnormalities were present in bone marrow cells from 27 patients (56%). The most frequent single anomaly was del (5 q) (10 cases), followed by monosomy 7 (3 cases), trisomy 8 (3 cases) and del (20 q) (2 cases). Complex anomalies were present in 6 patients. Morphologically, according to the French-American-British (FAB) classification: 17 cases were considered as refractory anemia (RA), 17 as RA with excess of blasts (RAEB), 2 as RAEB in transformation, 2 as acquired idiopathic sideroblastic anemia and 10 as chronic myelomonocytic leukemia. With regard to the FAB classification, del (5 q) was often associated with RA and complex cytogenetic anomalies with RAEB. When myelodysplasia was studied in individual myeloid lineages, del (5 q) was associated with hypolobulated megakaryocytes, monosomy 7 with micromegakaryocytes and complex chromosomal anomalies with the association of two or more features of dysmegakaryocytopoiesis. Del (11 q) was associated with increased iron storage and del (20 q) with marked dyserythropoiesis. No correlation was observed between cytogenetic anomalies and features of dysgranulocytopoiesis.     

Chromosome 11 rearrangements in the different haematological neoplasias

The cases of chromosome 11 abnormalities in leukemic bone marrow cells have constituted 14.0% in acute lymphoblastic leukemia (ALL), 18.7% in acute myeloid leukemia (AML), and 16.7% in refractory anemia (RA). The bands of the short arms 11p13, 11p14, llp15 and the long arms 11q14, 11q21, 11q23 were involved in chromosome rearrangements. The rearrangements of the band 11q23 were detected more often. Reciprocal translocations were found with the highest frequency, while para- and pericentic invertions, terminal and intestitial deletions occured with the lower incidence. Deletions were found in RA cases only. Comparison with the clinical features showed no correlation with the age and the main haematological indexes including the amount of blast cells in the initial period. The results have showed the poor prognosis of the abnormalities not only of 11q21, 11q23 in acute leukemia (AL), but of 11p13, 11p15 in AML as well, while not enough data on this subject is availalbe in the literature.     

Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid

5-azacytidine (AZA) has become standard treatment for patients with higher-risk myelodysplastic syndrome (MDS). Response rate is about 50% and response duration is limited. Histone deactylase (HDAC) inhibitors are attractive partners for epigenetic combination therapy. We treated 24 patients with AZA (100?mg/m(2), 5?days) plus valproate (VPA; continuous dosing, trough serum level 80-110?μg/ml). According to WHO classification, 5 patients had MDS, 2 had MDS/MPD, and 17 had acute myeloid leukemia (AML). Seven patients (29%) had previously received intensive chemotherapy, and five had previous HDAC inhibitor treatment. The overall response rate was 37% in the entire cohort but significantly higher (57%) in previously untreated patients, especially those with MDS (64%). Seven (29%) patients achieved CR (29%) and two PR (8%), respectively. Hematological CR was accompanied by complete cytogenetic remission according to conventional cytogenetics in all evaluable cases. Some patients also showed complete remission according to FISH on bone marrow mononuclear cells and CD34(+) peripheral blood cells, as well as by follow-up of somatic mitochondrial DNA mutations. Four additional patients achieved at least marrow remissions. Factors influencing response were AML (vs. MDS), marrow blast count, pretreatment, transfusion dependency, concomitant medication with hydroxyurea, and valproic acid (VPA) serum level. This trial is the first to assess the combination of AZA plus VPA without additional ATRA. A comparatively good CR rate, relatively short time to response, and the influence of VPA serum levels on response suggest that VPA provided substantial additional benefit. However, the importance of HDAC inhibitors in epigenetic combination therapy can only be proven by randomized trials.     

Community-acquired infections and their association with myeloid malignancies

Introduction: Antigenic stimulation is a proposed aetiologic mechanism for many haematological malignancies. Limited evidence suggests that community-acquired infections may increase the risk of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). However, associations with other myeloid malignancies including chronic myeloid leukaemia (CML) and myeloproliferative neoplasms (MPNs) are unknown. Materials and methods: Using the Surveillance, Epidemiology and End Result (SEER)-Medicare database, fourteen community-acquired infections were compared between myeloid malignancy patients [AML (n = 8489), CML (n = 3626) diagnosed 1992–2005; MDS (n = 3072) and MPNs (n = 2001) diagnosed 2001–2005; and controls (200,000 for AML/CML and 97,681 for MDS/MPN]. Odds ratios (ORs) and 95% confidence intervals were adjusted for gender, age and year of selection excluding infections diagnosed in the 13-month period prior to selection to reduce reverse causality. Results: Risk of AML and MDS respectively, were significantly associated with respiratory tract infections, bronchitis (ORs 1.20 [95% CI: 1.14–1.26], 1.25 [95% CI: 1.16–1.36]), influenza (ORs 1.16 [95% CI: 1.07–1.25], 1.29 [95% CI: 1.16–1.44]), pharyngitis (ORs 1.13 [95% CI: 1.06–1.21], 1.22 [95% CI: 1.11–1.35]), pneumonia (ORs 1.28 [95% CI: 1.21–1.36], 1.52 [95% CI: 1.40–1.66]), sinusitis (ORs 1.23 [95% CI: 1.16–1.30], 1.25 [95% CI: 1.15–1.36]) as was cystitis (ORs 1.13 [95% CI: 1.07–1.18], 1.26 [95% CI: 1.17–1.36]). Cellulitis (OR 1.51 [95% CI: 1.39–1.64]), herpes zoster (OR 1.31 [95% CI: 1.14–1.50]) and gastroenteritis (OR 1.38 [95% CI: 1.17–1.64]) were more common in MDS patients than controls. For CML, associations were limited to bronchitis (OR 1.21 [95% CI: 1.12–1.31]), pneumonia (OR 1.49 [95% CI: 1.37–1.62]), sinusitis (OR 1.19 [95% CI: 1.09–1.29]) and cellulitis (OR 1.43 [95% CI: 1.32–1.55]) following Bonferroni correction. Only cellulitis (OR 1.34 [95% CI: 1.21–1.49]) remained significant in MPN patients. Many infections remained elevated when more than 6 years of preceding claims data were excluded. Discussion: Common community-acquired infections may be important in the malignant transformation of the myeloid lineage. Differences in the aetiology of classic MPNs and other myeloid malignancies require further exploration.     

Depletion of cytotoxic T-cells does not protect NUP98-HOXD13 mice from myelodysplastic syndrome but reveals a modest tumor immunosurveillance effect

Myelodysplastic syndrome (MDS) and aplastic anemia (AA) patients both present with symptoms of bone marrow failure. In many AA patients, these features are thought to result from an oligoclonal expansion of cytotoxic T-cells that destroy haematopoietic stem or progenitor cells. This notion is supported by the observation that AA patients respond to immunosuppressive therapy. A fraction of MDS patients also respond well to immunosuppressive therapy suggesting a similar role for cytotoxic T-cells in the etiology of MDS, however the role of cytotoxic T-cells in MDS remains unclear. Mice that express a NUP98-HOXD13 (NHD13) transgene develop a MDS that closely mimics the human condition in terms of dysplasia, ineffective hematopoiesis, and transformation to acute myeloid leukemia (AML). We followed a cohort of NHD13 mice lacking the Rag1 protein (NHD13/Rag1KO) to determine if the absence of lymphocytes might 1) delay the onset and/or diminish the severity of the MDS, or 2) effect malignant transformation and survival of the NHD13 mice. No difference was seen in the onset or severity of MDS between the NHD13 and NHD13/Rag1KO mice. However, NHD13/Rag1KO mice had decreased survival and showed a trend toward increased incidence of transformation to AML compared to the NHD13 mice, suggesting protection from AML transformation by a modest immuno-surveillance effect. In the absence of functional Tcrb signaling in the NHD13/Rag1KO T-cell tumors, Pak7 was identified as a potential Tcrb surrogate survival signal.     

Hepcidin levels and their determinants in different types of myelodysplastic syndromes

Iron overload may represent an additional clinical problem in patients with Myelodysplastic Syndromes (MDS), with recent data suggesting prognostic implications. Beyond red blood cells transfusions, dysregulation of hepcidin, the key iron hormone, may play a role, but studies until now have been hampered by technical problems. Using a recently validated assay, we measured serum hepcidin in 113 patients with different MDS subtypes. Mean hepcidin levels were consistently heterogeneous across different MDS subtypes, with the lowest levels in refractory anemia with ringed sideroblasts (RARS, 1.43 nM) and the highest in refractory anemia with excess blasts (RAEB, 11.3 nM) or in chronic myelomonocytic leukemia (CMML, 10.04 nM) (P = 0.003 by ANOVA). MDS subtypes remained significant predictors of hepcidin in multivariate analyses adjusted for ferritin and transfusion history. Consistently with current knowledge on hepcidin action/regulation, RARS patients had the highest levels of toxic non-transferrin-bound-iron, while RAEB and CMML patients had substantial elevation of C-Reactive Protein as compared to other MDS subtypes, and showed lost of homeostatic regulation by iron. Growth differentiation factor 15 did not appear as a primary hepcidin regulator in this series. If confirmed, these results may help to calibrate future treatments with chelating agents and/or hepcidin modulators in MDS patients.     

Acute Myeloid Leukemia (AML) with Erythroid Predominance Exhibits Clinical and Molecular Characteristics that Differ from Other Types of AML

The clinical importance of erythroid predominance in bone marrow of patients with acute myeloid leukemia (AML) is controversial. These cases represent a heterogeneous group of diseases that historically have been classified into different categories. We studied 313 AML patients and specifically compared the clinical, cytogenetic, and molecular features of cases of AML with erythroid predominance, arbitrarily defined as ≥50% erythroid precursors, to AML cases without erythroid predominance. We also assessed 51 patients with a high-grade myelodysplastic syndrome (MDS), refractory anemia with excess blasts (RAEB). All neoplasms were classified according to the World Health Organization classification. With the exception of therapy-related AML/MDS, the presence of erythroid predominance in variously classified categories of AML was associated with a survival advantage. In addition, AML with erythroid predominance had a lower frequency of cytogenetic abnormalities as well as a lower frequency of mutations involving NPM1, NRAS and FLT3 as compared with AML without erythroid predominance. We conclude that the clinical, cytogenetic, and molecular features of AML with erythroid predominance in the non-therapy-related setting are much closer to those of a high-grade myelodysplastic syndrome than they are to other types of AML.