Leukemia in patients with acquired idiopathic sideroblastic anemia: an evaluation of prognostic indicators.

The initial clinical and laboratory data of 25 patients with acquired idiopathic sideroblastic anemia (AISA) were analyzed. Criteria for accepting the diagnosis were hyperferremia, ringed marrow sideroblasts, ineffective erythropoiesis, and exclusion of associated hematologic disorders. The findings of a mean age at onset of 70 years, increased mean corpuscular volume, relative neutropenia; and occasional splenomegaly at diagnosis corresponded with previous reports. During the followup for a median period of 32 months, 6 patients (25%) transformed to acute myelogenous or myelomonocytic leukemia after widely variable intervals. The initial data base of these patients was compared to that of the remaining 19 patients in order to isolate predictive features. Only a lesser degree of hyperferremia (P less than 0.001) made the group going on to leukemia distinctive. The median survival of these patients was 20 months. The median survival of 19 patients not developing leukemia was 72 months for males and 42 months for females. Hemochromatosis was diagnosed in four patients and was a primary or associated cause of death in three. Analysis of the transfusion history suggested that intrinsic iron leading was a major factor in these patients. We conclude that leukemic transformation in AISA is a common, poorly predictable event which required lengthy followup for detection. Hemochromatosis in AISA occurs frequently and shortens the median survival.     

Combined phenotypic and genotypic analysis of ringed sideroblasts in acquired idiopathic sideroblastic anemia

Bone marrow from an 81-year-old male with acquired idiopathic sideroblastic anemia was found to be mosaic for 45,X/46,XY cell lines. Analysis of ringed sideroblasts for the presence or absence of a quinicrine fluorescent Y body indicated that all sideroblastic cells had lost the Y chromosome. The demonstration that the ringed sideroblasts were cytogenetically abnormal in this patient provides evidence that the cytogenetic changes often found in patients with sideroblastic anemia may not be due to randomly acquired chromosome aberrations accompanying tissue aging unrelated to the disease process.     

Primary acquired sideroblastic anemia and myelodysplastic syndrome from a geriatric point of view

The median age of occurrence of primary acquired sideroblastic anemia is 74.4 years, with a range of 12 to 96 years (calculated from 452 cases). Of 445 cases, 60.4% were male, and 39.6% female. Not only primary acquired sideroblastic anemia, but the entire myelodysplastic syndrome must be considered as a disease of old age.     

Acquired hypochromic and microcytic sideroblastic anaemia responsive to pyridoxine with low value of free erythrocyte protoporphyrin: a possible subgroup of idiopathic acquired sideroblastic anaemia (IASA)

Patients with idiopathic acquired sideroblastic anaemia (IASA) usually show macrocytic or normocytic anaemia and increased free erythrocyte protoporphyrin (FEP). The mean cell haemoglobin concentration is normal or slightly low. Here we report a pyridoxine-responsive IASA patient with microcytic and hypochromic anaemia and low FEL level; these features are usually seen in cases of hereditary sideroblastic anaemia. Microcytosis increased during therapy.
There may be a subgroup of IASA with microcytic and hypochromic anaemia, low normal FEP and some response to pyridoxine like hereditary sideroblastic anaemia.     

Multiple domains of ADAMTS13 are targeted by autoantibodies against ADAMTS13 in patients with acquired idiopathic thrombotic thrombocytopenic purpura

Background

Type G immunoglobulins against ADAMTS13 are the primary cause of acquired (idiopathic) thrombotic thrombocytopenic purpura. However, the domains of ADAMTS13 which the type G anti-ADAMT13 immunoglobulins target have not been investigated in a large cohort of patients with thrombotic thrombocytopenic purpura.

Design and Methods

Sixty-seven patients with acquired idiopathic thrombotic thrombocytopenic purpura were prospectively collected from three major U.S. centers. An enzyme-linked immunosorbent assay determined plasma concentrations of anti-ADAMTS13 type G immunoglobulins, whereas immunoprecipitation plus western blotting determined the binding domains of these type G immunoglobulins.

Results

Plasma anti-ADAMTS13 type G immunoglobulins from 67 patients all bound full-length ADAMTS13 and a variant truncated after the eighth TSP1 repeat (delCUB). Approximately 97% (65/67) of patients harbored type G immunoglobulins targeted against a variant truncated after the spacer domain (MDTCS). However, only 12% of patients’ samples reacted with a variant lacking the Cys-rich and spacer domains (MDT). In addition, approximately 37%, 31%, and 46% of patients’ type G immunoglobulins interacted with the ADAMTS13 fragment containing TSP1 2-8 repeats (T2-8), CUB domains, and TSP1 5-8 repeats plus CUB domains (T5-8CUB), respectively. The presence of type G immunoglobulins targeted against the T2-8 and/or CUB domains was inversely correlated with the patients’ platelet counts on admission.

Conclusions

This multicenter study further demonstrated that the multiple domains of ADAMTS13, particularly the Cys-rich and spacer domains, are frequently targeted by anti-ADAMTS13 type G immunoglobulins in patients with acquired (idiopathic) thrombotic thrombocytopenic purpura. Our data shed more light on the pathogenesis of acquired thrombotic thrombocytopenic purpura and provide further rationales for adjunctive immunotherapy.     

Lack of efficacy of pyridoxine (vitamin B6) treatment in acquired idiopathic sideroblastic anaemia, including refractory anaemia with ring sideroblasts

Pyridoxine, or vitamin B6, is commonly used to treat acquired idiopathic sideroblastic anaemia (AISA, including refractory anaemia with ring sideroblasts), but the efficacy of this therapy in an unselected AISA population (i.e. patients without confirmed ALAS2 or other pyridoxine-responsive germline mutations) has not been established. We reviewed clinical data from 231 patients with AISA and found that 42% of 203 evaluable patients had been treated with pyridoxine. Only 6.8% of pyridoxine-treated patients experienced a haemoglobin improvement (≥ 1.5 g/dL) meeting 2006 International Working Group for Myelodysplastic Syndromes standardised response criteria. As some patients received combination therapy with erythropoietin or other agents, improvement could be attributed to pyridoxine monotherapy in only one patient (1.4%). Smaller, less meaningful increments in haemoglobin levels of 0.5 g/dL were observed in 13.5% of patients. Response to therapy did not correlate with International Prognostic Scoring System (IPSS) risk group or multilineage vs unilineage dysplasia. New symptomatic peripheral neuropathy was noted in 2.3% of patients treated with pyridoxine. In this large series of unselected patients with sideroblastic anaemia, pyridoxine therapy was ineffective and was associated with a risk of adverse effects. Pyridoxine therapy should be reserved for patients with known or suspected pyridoxine-responsive mutations.     

Specific antibodies to moesin, a membrane-cytoskeleton linker protein, are frequently detected in patients with acquired aplastic anemia

To identify novel autoantibodies in acquired aplastic anemia (AA), we screened the sera of patients with AA possessing small populations of paroxysmal nocturnal hemoglobinuria (PNH)-type cells for the presence of antibodies (Abs) which recognize proteins derived from a leukemia cell line, UT-7. Immunoblotting using proteins derived from lysates or culture supernatants of UT-7 cells revealed the presence of IgG Abs specific to an 80-kDa protein. Peptide mass fingerprinting identified this 80-kDa protein as moesin. Enzyme-linked immunosorbent assay (ELISA) using recombinant moesin showed high titers of antimoesin Abs in 25 (37%) of 67 patients with AA. Moesin was secreted from several myeloid leukemia cell lines other than UT-7, such as OUN-1 and K562, as an exosomal protein. The presence of antimoesin Abs was significantly correlated with the presence of PNH-type cells and antidiazepam-binding inhibitor-related protein-1 (DRS-1) Abs. Patients with AA that did not show any of these 3 markers tended to respond poorly to immunosuppressive therapy. These findings suggest that a B-cell response to moesin, possibly derived from hematopoietic cells, frequently occurs in patients with AA and that detection of antimoesin Abs in combination with other markers may be useful in diagnosing immune pathophysiology in patients with AA.     

Acute monoblastic leukemia with a single chromosomal rearrangement involving breakpoints on chromosomes 8 and 16, 46, XX, t(8;16)(p11;p13)

We report a case of acute nonlymphoblastic leukemia (M5) with a rare cytogenetic abnormality involving chromosomes 8 and 16, t(8;16)(p11;p13). The leukemic blasts were determined to be monocytic by cytochemical and immunochemical studies. Morphological changes of the leukemic cells in response to phorbol myristate acetate further supported their identification as monocytic in nature. This chromosomal abnormality has apparently been reported only thrice in the literature. Translocation (8;16)(p11;p13), though rare, may be of primary importance in the process of leukemogenesis in some cases of histiocytic/monocytic malignancies.     

Variable breakpoints target PAX5 in patients with dicentric chromosomes: a model for the basis of unbalanced translocations in cancer

The search for target genes involved in unbalanced acquired chromosomal abnormalities has been largely unsuccessful, because the breakpoints of these rearrangements are too variable. Here, we use the example of dicentric chromosomes in B cell precursor acute lymphoblastic leukemia to show that, despite this heterogeneity, single genes are targeted through a variety of mechanisms. FISH showed that, although they were heterogeneous, breakpoints on 9p resulted in the partial or complete deletion of PAX5. Molecular copy number counting further delineated the breakpoints and facilitated cloning with long-distance inverse PCR. This approach identified 5 fusion gene partners with PAX5: LOC392027 (7p12.1), SLCO1B3 (12p12), ASXL1 (20q11.1), KIF3B (20q11.21), and C20orf112 (20q11.1). In each predicted fusion protein, the DNA-binding paired domain of PAX5 was present. Using quantitative PCR, we demonstrated that both the deletion and gene fusion events resulted in the same underexpression of PAX5, which extended to the differential expression of the PAX5 target genes, EBF1, ALDH1A1, ATP9A, and FLT3. Further molecular analysis showed deletion and mutation of the homologous PAX5 allele, providing further support for the key role of PAX5. Here, we show that specific gene loci may be the target of heterogeneous translocation breakpoints in human cancer, acting through a variety of mechanisms. This approach indicates an application for the identification of cancer genes in solid tumours, where unbalanced chromosomal rearrangements are particularly prevalent and few genes have been identified. It can be extrapolated that this strategy will reveal that the same mechanisms operate in cancer pathogenesis in general.     

Zinc-induced sideroblastic anemia: Report of a case,review of the literature,and description of the hematologic syndrome

Zinc ingestion has become increasingly popular in the lay and food faddist population. Herein described by way of a case report and review of the 13 cases in the literature is the syndrome of severe anemia associated with excessive and prolonged intake of oral zinc. The syndrome is characterized by anemia, granulocytopenia, and bone marrow findings of vacuolated precursors and ringed sideroblasts. Serum analysis reveals increased zinc levels, decreased copper levels, and a decrease in ceruloplasmin. The mechanism appears to be zinc-induced copper deficiency, which is instrumental in producing the profound bone marrow abnormalities, as zinc itself is of low toxicity. Importantly, the syndrome is totally reversible with cessation of zinc intake. Hematologists should be aware of this form of reversible sideroblastic anemia. © 1994 Wiley-Liss, Inc.     

A higher prevalence of abnormal regional cerebral blood flow in patients with syndrome X and abnormal myocardial perfusion

To test the hypothesis that syndrome X is a systemic vascular disorder, technetium-99m ethyl cysteinate dimer (Tc-99m ECD) brain single photon emission computed tomography (SPECT) was used to detect abnormal regional cerebral blood flow (rCBF) in 30 patients with syndrome X. These patients were separated into group 1, 20 patients with definite myocardial perfusion defects diagnosed by thallium-201 (Tl-201) myocardial perfusion SPECT; and group 2, 10 patients without any myocardial perfusion defects. Tc-99m ECD brain SPECT demonstrated hypoperfusion brain lesions in 95% (19/20) and 20% (2/10) of patients in groups 1 and 2, respectively. This difference in the cidence between the two groups was significant. In group 1 and 2 patients, parietal lobes were the most common hypoperfusion areas, while the cerebellum was the least common hypoperfusion area of the brain. Syndrome X is a systemic vascular disorder with a high incidence of hypoperfusion lesions of the brain based on the findings of Tc-99m ECD brain SPECT, and is usually coincident with myocardial defects based on the Tl-201 myocardial perfusion SPECT findings.     

A heteroplasmic point mutation of mitochondrial tRNALeu(CUN) in non-lymphoid haemopoietic cell lineages from a patient with acquired idiopathic sideroblastic anaemia

Acquired idiopathic sideroblastic anaemia (AISA) has been proposed to be a disorder of mitochondrial DNA (mtDNA). The hallmark of mitochondrial iron overload may be attributable to a respiratory chain defect leading to impaired reduction of ferric iron (Fe^3 +) to ferrous iron (Fe^2 +), which is essential to the last step of mitochondrial haem biosynthesis. In a 71-year-old patient we identified a point mutation in one of the two mitochondrial transfer-RNAs coding for leucine (tRNA^leu(CUN)). The mutation involves a G → A transition in the anticodon loop, immediately adjacent to the anticodon triplet (mtDNA position 12301). The mutated guanine is highly conserved in a wide range of species. The mutation is heteroplasmic, i.e. there is a mixture of normal and mutated mitochondrial genomes (ratio c. 50:50). Heteroplasmy of mtDNA is not found in normal individuals, but is a typical feature of mitochondrial cytopathies. The point mutation was present in the patient's bone marrow and whole blood samples, in purified platelets, and in the granulocyte/erythrocyte pellet after mononuclear cell separation by density gradient centrifugation. The mutation was not found in T- and B-lymphocytes isolated by immunomagnetic bead separation. It was also absent from buccal mucosa cells and cultured skin fibroblasts. This pattern of involvement suggests that the mutation occurred in a self-renewing myeloid stem cell of the CFU-GEMM type.