Pure red cell aplasia in childhood and adolescence: pathogenesis and approaches to diagnosis.
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Adolescent↗
Biomedical subjects
M H Freedman
Publications and source records attributed to M H Freedman.
The induction of CD10 on a pre-B leukemia cell line occurs with progression of the disease in scid mice.
We have previously demonstrated the engraftment and dissemination of human pre-B acute lymphoblastic leukemia (ALL) cells into scid mice. In the current study, the temporal pattern of infiltration of a CD10- pre-B leukemia line (G2) in various murine tissues and the progression of the disease in the whole animal were monitored by quantifying human CD44 mRNA expression by the polymerase chain reaction (PCR). Irradiated scid mice were injected intravenously with 10(6) G2 cells and killed 3 days to 10 weeks later. After 2 weeks, leukemic cells were found mostly in bone marrow, but also in lung. At 6 to 7 weeks, spleen and lung contained 30% human RNA, while peripheral blood, liver, and kidney contained 2-3%. Infiltration to brain and thymus was observed at 8-9 weeks. In terms of the whole animal, spleen and liver were the major sites of tumor burden. The induction of CD10 expression was previously observed in transplanted CD10- G2 leukemic cells recovered from scid thymus at 10-12 weeks, which corresponds to the terminal stage of disease. In this study, the CD10 expression on the leukemic cells was monitored at earlier time points by flow cytometry and quantitative PCR. Induction of CD10 was first observed in bone marrow, spleen, peripheral blood, and liver at 6-7 weeks (10-fold), at the time of the onset of dissemination of the leukemia. Despite the presence of 30% human RNA in lung at 6-7 weeks, CD10 induction was not significant in that site before 10 weeks. Increased levels of CD10 were seen in all tissues between 8 and 10 weeks; the highest levels were observed in leukemic cells proliferating in thymus (113-fold) and in those found in circulation. These findings suggest that initial induction of CD10 occurs in hematopoietic tissues at the time of rapid proliferation of the leukemic cells and their infiltration of several tissues. At later time points, the increase in CD10 expression is seen on the leukemic cells found in all peripheral organs suggesting an association with disease progression.
Animals↗
Unexpected complications after bone marrow transplantation in transfusion-dependent children.
Ten patients on transfusion-chelation programs were treated with bone marrow transplantation (BMT). The busulfan-cyclophosphamide conditioning regimen was inadequate in the 6 beta thalassemia major patients, resulting in marrow rejection problems for 3. Post BMT one patient remains with thalassemia major and two have mixed chimerism with a clinical status of thalassemia intermedia. Three patients have thalassemia minor from their donors, but one required a second BMT to achieve this state. Two of the four Diamond Blackfan Syndrome patients died of BMT-related complications. Two achieved normal hematopoiesis, one at the price of chronic graft vs host disease. Because of the excellent results of iron chelation in our patients, we question whether such patients with access to the state of the art transfusion-chelation programs should continue to be transplanted. This situation requires continuing evaluation.
Blood Transfusion↗
Trial of recombinant human erythropoietin: three patients with thalassemia intermedia.
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Adolescent↗
Interleukin 6 induces myeloid differentiation of a human biphenotypic leukemic cell line.
The human leukemic cell line B1, is characterized by a specific 4;11 chromosomal translocation, immature myeloid/pre-B biphenotypic features, expression of multiple cytokine receptors and IL-1-dependent autocrine growth regulation [Cohen et al. (1991) Blood 78, 94]. Exposure of B1 cells to low concentrations of IL-6 abolished the leukemic cells ability to form colonies in semi-solid medium and slowed down their proliferation rate in suspension. Associated with these changes in growth characteristics, the B1 cells differentiated along the myeloid lineage as judged by the induction of the myeloid-specific surface antigens CD33, CD13 and CD11b, as well as histochemical and morphological changes characteristic of myeloid cells. The induction of differentiation was specific to IL-6 since none of the other cytokines which inhibited B1 cell growth (IL-7, gamma IFN and TNF alpha) were able to induce myeloid or lymphoid differentiation in these cells. The IL-6-induced differentiation was completed over a two week period and was essentially irreversible. Together with the phenotypic changes, IL-6 induced the expression of the protein tyrosine phosphatase (CD45) which may be associated with altered growth observed in IL-6-treated cells. Induction of terminal differentiation of leukemic cells by recombinant bioregulators has therapeutic implications and merits further study.
Bone Marrow↗
Growth failure and bony changes induced by deferoxamine.
We reviewed the linear growth and growth plate morphology in all children with homozygous beta thalassemia followed in Toronto, for whom monthly height percentiles were available before, and for a 36-month period after, the initiation of nightly subcutaneous deferoxamine therapy. All patients were less than 7 years of age when begun on deferoxamine, and had received nightly deferoxamine for a minimum of 36 months. Marked abnormalities of the metaphyseal growth plate were readily observed in the distal ulnar, radial, and tibial metaphyses in 11 of 37 patients in whom a significant decline in mean height percentile was also noted. (In 10 of these 11 patients, height was less than the 15th percentile after 36 months.) These 11 patients had received a significantly greater (p less than 0.025) initial and average daily dose of deferoxamine, and had maintained a significantly lower (p less than 0.025) mean serum ferritin concentration over the 36 months, than the remainder of the cohort. To determine whether deferoxamine played a causative role in growth failure, growth in patients who began deferoxamine before the age 2 years was compared to that of patients who began after age 5 years, for the period between 2 and 5 years of age. Only patients begun on deferoxamine prior to age 2 years demonstrated a significant (p less than 0.01) decline in height percentile by the third year, implicating deferoxamine therapy as the cause of growth failure. We conclude that both the decline in height percentile and the bony changes observed in well-chelated patients are directly related to deferoxamine therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Alkaline Phosphatase↗
Central role of tumour necrosis factor, GM-CSF, and interleukin 1 in the pathogenesis of juvenile chronic myelogenous leukaemia.
In previous studies on patients with juvenile chronic myelogenous leukaemia (JCML), we found excessive proliferation of malignant monocyte-macrophage elements in the absence of exogenous growth factor, and impaired growth of normal haematopoietic progenitors. In the current study, six newly-diagnosed JCML patients were investigated to characterize the disease further. In co-cultures, JCML cell culture supernatant as well as patient plasma obtained at diagnosis produced a striking reduction in numbers of control marrow BFU-E, CFU-GM, CFU-Meg and CFU-GEMM colonies. Monoclonal anti-tumour necrosis factor alpha neutralizing antibodies (anti-TNF-alpha Ab) abolished these inhibitory properties. In sharp contrast, JCML supernatants exerted a marked growth-promoting effect on autologous JCML cells cultured in clonogenic assays. Anti-TNF-alpha Ab and anti-granulocyte-macrophage colony-stimulating factor neutralizing antibodies (anti-GM-CSF Ab) both reversed the stimulating effect. Recombinant GM-CSF and recombinant TNF alpha produced a profound increase in JCML colonies when tested individually and anti-GM-CSF Ab reversed the TNF-alpha effect. Expression studies of TNF-alpha and TNF-alpha receptor genes of cultured JCML cells demonstrated mRNAs for both. Further, TNF-alpha activity was assayed in a wide variety of cell culture supernatants and in normal and patients' plasma, and only the JCML specimens showed increased TNF-alpha values. Recombinant interleukin-1 alpha (IL-1 alpha) also stimulated JCML colony growth, but polyclonal anti-IL-1 neutralizing antibodies did not suppress JCML colony numbers nor did it reverse the effects of TNF-alpha or GM-CSF. The evidence indicated that the JCML monokine which inhibits normal haematopoiesis is TNF-alpha and that the endogenously-produced TNF-alpha and GM-CSF from JCML cells play an important role in the pathogenesis of the disease by acting as autocrine growth factors. IL-1 alpha also stimulates JCML cell proliferation as an accessory factor and augments the effect of GM-CSF, TNF-alpha or both.
Base Sequence↗
Differential kinetics of engraftment and induction of CD10 on human pre-B leukemia cell lines in immune deficient scid mice.
The sensitivity of the scid mouse model was assessed by comparing the growth of two pre-B acute lymphoblastic leukemia (ALL) cell lines, A1 and G2, established from patients at relapse. When cell numbers varying from 10(4) to 10(7) were injected intravenously into scid mice, advanced growth and dissemination of leukemia was observed at 10-12 weeks with the G2 cells. Bone marrow, spleen and thymus contained high levels of human leukemic cells and infiltration into lung, kidney, liver, and brain was observed. Two of three mice grafted with only 100 cells showed high levels of infiltration at 15 weeks, suggesting that 100 G2 cells was near the limiting cell number that could produce disseminated leukemia. With the A1 line, a minimum of 10(5) cells was needed to obtain dissemination to liver, lung, brain, and kidney; a low level of spleen infiltration occurred and thymus invasion was not observed. In vitro, both lines showed a density dependent growth in clonogenic assays but the cloning efficiency of the A1 line was 10-fold higher than for G2 cells. These results indicate that G2 and A1 lines have a dissimilar aggressiveness in vivo which does not correlate with clonogenic assay in vitro. Neither G2 nor A1 lines, growing in vitro, expressed CD10/CALLA on their surface, despite low levels of antigen on the freshly obtained relapse samples. Although A1 cells remained CD10-negative in the scid mice, G2 cells showed detectable levels of CD10, particularly on those cells found in the thymus. Several subclones of the G2 line were derived from isolated colonies in vitro; they were found to be CD10- in vitro, but to become CD10+ when proliferating into scid mouse thymus, suggesting the induction of CD10 by the murine microenvironment.
Animals↗
Bone marrow from children in relapse with pre-B acute lymphoblastic leukemia proliferates and disseminates rapidly in scid mice.
Bone marrow samples from patients with pre-B acute lymphoblastic leukemia (pre-B ALL), either at diagnosis or at relapse, were transplanted into scid mice to determine whether these freshly obtained leukemic cells could proliferate in vivo and whether there were any differences in their in vivo growth characteristics. Cells from three patients who relapsed within 13 months of diagnosis proliferated rapidly in the murine bone marrow, spleen, and thymus, invaded peripheral organs, and resulted in morbidity and mortality of the animals within 4 to 16 weeks. Cells from two patients who relapsed 3.5 years after diagnosis grew much slower than the early relapse samples, taking up to 30 weeks to infiltrate the bone marrow of recipient mice. In contrast, leukemic cells were absent or were detected at low numbers in scid mice transplanted with cells obtained at diagnosis from three patients who have not yet relapsed. These results show an increased ability of leukemic cells from patients with aggressive lymphoblastic leukemia of poor prognosis to proliferate in scid mice.
Adolescent↗
Constitutive expression and role in growth regulation of interleukin-1 and multiple cytokine receptors in a biphenotypic leukemic cell line.
A cell line (B1) was established from the bone marrow of a patient with a relapse of acute leukemia characterized by a 4;11 chromosomal translocation and biphenotypic features of early B and myeloid lineages. Analysis of the growth requirements of this cell line showed density-dependent growth and secretion of an autostimulatory growth factor, suggesting an autocrine mechanism. Several lines of evidence implicate the participation of interleukin-1 (IL-1) in the autocrine growth regulation of B1 cells. These cells constitutively express the messenger RNA (mRNA) for IL-1 and IL-1 receptor and secrete IL-1; recombinant IL-1 stimulated the growth of colonies when cells were seeded at low density, and anti-IL-1 antibodies inhibited the growth of colonies with cells seeded at higher density. B1 cells do not express detectable levels of mRNA for any of the other cytokines tested, and other cytokines failed to support the growth of B1 cells at low density. In addition, B1 cells express multiple cytokine receptor genes, including the receptors for IL-6, IL-7, tumor necrosis factor and gamma-interferon. Addition of the respective cytokines to the B1 cells resulted in inhibition of the growth of leukemic cells in vitro. The multiplicity of growth-inhibitory cytokine receptors on this leukemic cell line might be due to its biphenotypic lineage and may suggest new therapeutic possibilities in controlling leukemic cell proliferation.
Acute Disease↗
Rarity of systemic lupus erythematosus after oral iron chelator L1.
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Deferiprone↗
A new frameshift beta zero-thalassemia mutation (codons 27-28 +C) found in a Chinese family.
A new beta zero-thalassemia mutation, a frameshift mutation with an insertion of a single cytosine nucleotide in codon 27-28, is described. The propositus, who is compound heterozygous for this mutation and the IVSII-654 C----T beta zero-thalassemia mutation, has the phenotype of severe beta-thalassemia major.
Adult↗
Fibrolamellar carcinoma of the liver in a patient with Fanconi anemia.
A 9-year-old boy with Fanconi anemia treated with oxymethalone, a synthetic androgen, died of intracerebral hemorrhage. At autopsy, the liver contained several adenomas and a large fibrolamellar hepatocellular carcinoma, as well as phlebectatic peliosis hepatis. The 11 previously reported cases of hepatocellular carcinoma in Fanconi anemia were not, apparently, of the fibrolamellar type, which has a better prognosis, occurs in children of both sexes, and generally is not associated with cirrhosis. The malignant potential of primary liver tumors associated with Fanconi anemia as well as the nature of their relationship to Fanconi anemia and to anabolic steroid therapy is discussed.
Carcinoma, Hepatocellular↗
Fanconi's anaemia and pregnancy.
We have identified six new cases of Fanconi's anaemia (FA) who had pregnancies, and reviewed 11 others from the literature. At least 110 FA females have reached 16 years of age or more, of whom 15% became pregnant. There were a total of 26 pregnancies, resulting in 19 births and 18 surviving children. Anaemia and/or thrombocytopenia worsened during pregnancy in 10 patients, but five subsequently improved: seven had no haematological problems. Seven of the FA patients who had pregnancies died subsequently from cancer, and two from thrombocytopenic bleeding 3 and 20 years later. There were no peripartum deaths. Pregnancy in FA is clearly possible, with increased risks that are manageable from both the haematological and the obstetric aspects.
Adolescent↗
Acute lymphoblastic leukemia blast cells do not inhibit bone marrow hematopoietic progenitor colony formation.
In newly diagnosed patients with acute lymphoblastic leukemia (ALL), bone marrow (BM) morphology always shows "replacement" by blasts with decreased or absent normal hematopoietic elements. To answer the question of whether ALL blasts inhibit replication and maturation of normal marrow progenitors, we studied the interaction of normal marrow with BM specimens from 16 new cases of ALL. Irradiated ALL blasts, supernatant derived from ALL blasts in suspension cultures, and conditioned medium prepared from ALL blasts augmented the colony-forming ability of normal marrow erythroid burst-forming unit (BFU-E), granulocyte-macrophage colony-forming unit (CFU-GM), megakaryocyte colony-forming unit (CFU-MK), and multilineage colony-forming unit (CFU-GEMM) progenitors. In sharp contrast to published data on the suppressive effects of acute myeloblastic leukemia cells on normal hematopoiesis in vitro, our results indicate that the growth advantage of ALL cells over normal marrow elements is not mediated through an inhibitory mechanism derived from leukemia cells.
Adolescent↗
Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients.
The efficacy of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) was compared with that of subcutaneous desferrioxamine in 26 patients with transfusional iron overload. Immediately after red-cell transfusion, 20 patients were randomised to receive either desferrioxamine (50 mg/kg daily as a 12 h subcutaneous infusion), or L1 (50 mg/kg daily by mouth). Patients were evaluated during treatment with the other drug after transfusion the next month. Mean (SD) daily urinary iron excretion was lower during L1 than during desferrioxamine (12.3 [6.7] vs 18.2 [15.3] mg/day). In 5 patients the dose of L1 was raised from 50 to 75 mg/kg daily; mean urinary iron excretion rose from 13.8 (7.0) mg/day to 26.7 (17.8) mg/day, comparable with that during desferrioxamine (24.9 [24.3] mg/day). Faecal iron excretion rose slightly over baseline in 6 patients studied during L1 administration (from 8.5 [0.9] mg/day to 12.2 [0.9] mg/day). Pharmacokinetic studies showed an elimination half-life for L1 of 117-237 min. Studies in dogs and in volunteers showed no absorption of the L1-iron complex, excluding a contribution of absorption of intraluminal complexes of L1 and food iron to urinary iron excretion. Further animal toxicity testing is needed before L1 can be studied in a broader group of patients.
Adolescent↗
Effect of age at the start of iron chelation therapy on gonadal function in beta-thalassemia major.
BACKGROUND: Patients with transfusion-dependent thalassemia major tend to have abnormal growth and sexual maturation at puberty, presumably as a result of pituitary iron overload. This study was designed to determine whether chelation therapy with deferoxamine before the age of puberty would ameliorate this problem. METHODS: We examined 40 patients over 14 years of age with transfusion-dependent thalassemia major. The 19 patients in group A (mean [+/- SD] age at study, 17.0 +/- 1.5 years) had begun nightly treatment with subcutaneous deferoxamine before the age of 10 (mean age at start of treatment, 7.5 +/- 1.8 years). The 21 patients in group B (mean age, 24.1 +/- 3.8 years) had begun treatment after the age of 10 (mean age at start of treatment, 14.4 +/- 4.7 years). RESULTS: The abnormal findings were essentially confined to sexual development. The final height did not differ between groups or from the mean parental height in each group. Ninety percent of the patients in group A had normal sexual development, as compared with 38 percent of those in group B (P = 0.001). Outcomes were correlated with indexes of iron overload; the patients in group A had lower serum ferritin levels before chelation treatment (P = 0.01) and lower average serum ferritin levels during treatment (P = 0.005). CONCLUSIONS: Beginning chelation treatment with deferoxamine before the age of puberty can help children with transfusion-dependent thalassemia major to attain normal sexual maturation.
Adolescent↗
The expression of c-fos, c-jun, and c-myc genes is regulated by heat shock in human lymphoid cells.
The effect of heat shock on the expression of the nuclear protooncogenes c-fos, c-jun, and c-myc was studied in human lymphoid cells. Heat shock caused an increase in c-fos and c-jun mRNA levels and a decrease in c-myc mRNA levels in pre-B (Hyon) and T (DND-41) cell lines as well as in freshly isolated normal human thymocytes. The changes in the mRNA levels of these protooncogenes in Hyon cells were most pronounced at 42 and 43 degrees C; kinetic analysis demonstrated that the changes could be detected within 30 min of heat shock. Altered transcription of c-fos and c-myc genes was the primary effect of heat shock. Secondarily, heat shock of Hyon cells stabilized the c-myc mRNA level by increasing its half-life from 24 to 45 min. The overall effect of heat shock on c-myc mRNA level, however, was a marked inhibition of its transcription. These results demonstrate that the transcription of nuclear protooncogenes is regulated by heat shock indicating a role for nuclear protooncogenes in the stress response of lymphoid cells.
B-Lymphocytes↗