Induction of a functional vitamin D receptor in all-trans-retinoic acid-induced monocytic differentiation of M2-type leukemic blast cells.
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Different types of acute myeloid leukemia blast cells were induced to differentiate in vitro with all-trans-retinoic acid (ATRA) and vitamin D3 (VD). M0/M1 leukemic cells are not sensitive to differentiating agents, whereas M3 leukemic cells are induced to undergo granulocytic differentiation after ATRA treatment but are not sensitive to VD. M2 leukemic blast cells behave differently because they undergo monocytic differentiation with both the differentiation inducers. To gain some insight into the maturation of M2-type leukemic cells, we studied the molecular mechanisms underlying monocytic differentiation induced by ATRA and VD in spontaneous M2 blast cells as well as in Kasumi-1 cells (an acute myeloid leukemia M2-type cell line). Our results indicate that ATRA as well as VD efficiently increases the nuclear abundance of VD receptor (VDR) and promotes monocytic differentiation. VDR is functionally active in ATRA-treated Kasumi-1 cells because it efficiently heterodimerizes with retinoid X receptor, binds to a DR3-type vitamin D-responsive element, and activates the transcription of a vitamin D-responsive element-regulated reporter gene. Consistent with these findings, VD-responsive genes are induced by ATRA treatment of Kasumi-1 cells, suggesting that the genetic program underlying monocytic differentiation is activated. The molecular mechanism by which ATRA increases the nuclear abundance of a functional VDR is still unknown, but our data clearly indicate that the M2 leukemic cell context is only permissive of monocytic differentiation. (+info)
Tularemia--an unusual cause of a solitary pulmonary nodule in the post-transplant setting.
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We report a case of tularemia presenting as a solitary pulmonary nodule following syngeneic PBSC transplant. Seven months after undergoing a syngeneic PBSC transplant for AML, our patient presented with fever without localizing signs. Chest X-ray revealed a solitary pulmonary nodule. Culture of a CT guided needle aspiration revealed Francisella tularensis. The patient was successfully treated with ciprofloxacin. His fever resolved and clearance of the nodule was documented on a CT scan 2 months after diagnosis and initiation of treatment. To our knowledge, this is the only reported case of tularemia occurring in the post-transplant setting. The possible relationship between transplant-induced immune dysfunction and the occurrence of this rare infection is discussed. (+info)
Immunological reconstitution after cord blood transplantation for an adult patient.
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We transplanted 4.1x10(7) unrelated umbilical cord blood cells into a 27-year-old patient suffering from transformed acute myelocytic leukemia. The thawing method was the same as described by Rubinstein et al (Proc. Natl. Acad. Sci. USA 1995; 92: 10119-10122). ANC reached over 500x10(9)/l on day 19, and the patient was free from RBC and platelet transfusion on days 26 and 38, respectively. Cytogenetic and molecular analysis after transplant revealed complete chimerism. The CD3+CD4+ lymphocyte count became greater than 100x10(9)/l at 5 weeks after transplantation. The CD3+CD8+ count became greater than 500x10(9)/l at 7 weeks and thereafter progressively increased in spite of administration of CYA. This immunological reconstitution pattern after umbilical cord blood transplantation was different from that after bone marrow transplantation, and resistance of CD3+CD8+ lymphocytes to CYA was the distinguishing characteristic. The rapid hematological recovery and immunological reconstitution may be attributed to the high dose of transfused nucleated cells and umbilical cord blood transplantation may become a promising method for treatment for such cases. (+info)
3q21 and 3q26 cytogenetic abnormalities in acute myeloblastic leukemia: biological and clinical features.
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BACKGROUND AND OBJECTIVE: Acute myeloblastic leukemia (AML) with features of myelodysplastic syndrome (MDS) and abnormalities of megakaryocytopoiesis is often characterized by cytogenetic aberrations of the 3q21 and 3q26 bands involving inv(3)(q21q26) and (3;3)(q21;q26). These aberrations have been described in all FAB subtypes with the exception of M3, and in MDS and in megakaryoblastic crisis of chronic myeloid leukemia. We reviewed the biological and clinical features of 10 cases of AML with inv(3)(q21q26) and t(3;3)(q21;q26). DESIGN AND METHODS: Four hundred and sixteen patients with AML were studied in our Institute by cytogenetic analysis and 10 (2.4%) showed inv(3)(q21q26) (7 patients) or t(3;3)(q21;q26) (3 patients): 7 males, 3 females; median age, 43.5 yrs. We also used RT-PCR to investigate the pattern of expression of the EVI-1 gene in 5 patients. RESULTS: Additional chromosomal changes were demonstrated in 6 patients. In 5/10 cases a preceding MDS had been observed. A possible occupational exposure was established in 2 patients (a farmer and an histologist employing organic solvents) and another patient had a therapy-related leukemia. AML subtype was M1 in 9 patients and M2 in 1. A variable excess of micromegakaryocytes was observed in all the patients. In 5 patients the platelet count was normal or increased (median number: 172. 5x10(9)/L; range 55-440). Expression of EVI-1 gene was present in all the 5 patients studied. The clinical course and outcome was extremely poor: 9/10 patients were resistant and 1 patient showed a partial remission after induction therapy. Of the 9 patients resistant to the first line chemotherapy, 7 were also resistant to the second line chemotherapy. Three patients obtained a morphologic complete remission after third line chemotherapy (duration 1, 3 and 6 months); 2 of them were submitted to autologous bone marrow transplantation, but relapsed after 1 and 3 months. The median overall survival was 5.5 months. INTERPRETATION AND CONCLUSIONS: Our findings evidence a strong correlation between 3q21q26 chromosomal aberrations, abnormalities of megakaryocytopoiesis and lack of response to conventional chemotherapy and support the diagnostic and prognostic relevance of chromosome characterization in the classification of AML. (+info)
Allogeneic bone marrow transplant or second autograft in patients with acute leukemia who relapse after an autograft. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).
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Among 2752 patients with acute leukemia who had recurrent leukemia after autograft in remission and were reported to the EBMT, 94 underwent an allogeneic bone marrow transplant and 74 received a second autograft. Recipients of HLA-mismatched related or unrelated bone marrow had an increased transplant-related mortality (TRM, P = 0.017) and a decreased leukemia-free survival (LFS, P = 0.03), compared to recipients of HLA matched related or unrelated bone marrow. Outcome in recipients of HLA-compatible related or unrelated bone marrow was compared to those receiving a second autograft. TRM at 2 years was 51 +/- 8% in recipients of matched allografts and 26 +/- 6% following a 2nd autograft (P < 0.05). Two-year LFS was 27 +/- 7% and 35 +/- 6% in the two groups, respectively (NS). Multivariate analysis in these two groups showed that TRM was increased in patients who were in 2nd or later remission at 1st autograft (P < 0. 05) and allograft recipients (P < 0.05). Relapse was more common in patients with ALL (P < 0.001), above 25 years of age (P < 0.02), autograft performed later than 1991 (P < 0.05), and in second autografts (P < 0.05). LFS was decreased in patients >25 years of age (P < 0.01), if the interval from first autograft to relapse was 8 months or less (P < 0.01) and if TBI was used at first autograft (P < 0.05). (+info)
Growth characteristics of acute myelogenous leukemia progenitors that initiate malignant hematopoiesis in nonobese diabetic/severe combined immunodeficient mice.
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The use of immunodeficient mice, particularly of the nonobese diabetic/severe combined immunodeficient (NOD/SCID) strain, has allowed detection of very primitive malignant progenitors from patients with acute myelogenous leukemia (AML). To define the sensitivity and reproducibility with which the engraftment of different AML cells can be detected, 61 different samples from patients with newly diagnosed AML representing a variety of cytogenetic and French-American-British (FAB) subtypes were injected into NOD/SCID mice. Eight weeks after intravenous injection of 10(7) AML cells, the average percent of human cells in mouse bone marrow was 13.3%, with 70% of samples showing easily detectable engraftment of CD45(+) cells. AML samples with cytogenetic changes associated with a poor clinical prognosis tended to engraft to higher levels than those with changes associated with a good prognosis. Cells with FAB subtypes M3 and, to a lesser extent, M2, engrafted more poorly (P =.002 and.06, respectively) than those from other subtypes. Intraperitoneal injection of human interleukin-3 and Steel factor thrice weekly for 4 weeks did not enhance the levels of AML cell engraftment. However, AML samples that showed cytokine-independent colony growth in methylcellulose assay or expressed growth-factor mRNA in malignant blasts achieved significantly higher levels of engraftment than those which were cytokine dependent in culture or failed to express cytokine message (P <.03 and P <.02, respectively). In 6 patient samples, the frequency of NOD/SCID leukemia-initiating cells (NOD/SL-IC) varied from 0.7 to 45 per 10(7) cells, which was 200- to 800-fold lower than the frequency of AML long-term culture-initiating cells (AML LTC-IC) in the same samples. Each NOD/SL-IC will produce more than 10(6) leukemic blasts as well as many AML-CFC and AML LTC-IC as detected 8 weeks postinjection into mice. Serial transplant experiments showed the ability of NOD/SL-IC to maintain their own numbers over at least 3 to 4 weeks in vivo. The ability of these progenitors to self-renew combined with their potential to differentiate to produce large numbers of more mature progenitors and leukemic blasts suggests that the NOD/SL-IC assay identifies leukemic 'stem cells' that may maintain the malignant clone in human patients. The further use of this assay should facilitate studies of AML stem cell biology and the evolution of novel therapeutic strategies. (+info)
CD34(+) acute myeloid and lymphoid leukemic blasts can be induced to differentiate into dendritic cells.
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CD34(+) hematopoietic stem cells from normal individuals and from patients with chronic myelogenous leukemia can be induced to differentiate into dendritic cells (DC). The aim of the current study was to determine whether acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells could be induced to differentiate into DC. CD34(+) AML-M2 cells with chromosome 7 monosomy were cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor alpha (TNFalpha), and interleukin-4 (IL-4). After 3 weeks of culture, 35% of the AML-M2 cells showed DC morphology and phenotype. The DC phenotype was defined as upmodulation of the costimulatory molecules CD80 and CD86 and the expression of CD1a or CD83. The leukemic nature of the DC was validated by detection of chromosome 7 monosomy in sorted DC populations by fluorescence in situ hybridization (FISH). CD34(+) leukemic cells from 2 B-ALL patients with the Philadelphia chromosome were similarly cultured, but in the presence of CD40-ligand and IL-4. After 4 days of culture, more than 58% of the ALL cells showed DC morphology and phenotype. The leukemic nature of the DC was validated by detection of the bcr-abl fusion gene in sorted DC populations by FISH. In functional studies, the leukemic DC were highly superior to the parental leukemic blasts for inducing allogeneic T-cell responses. Thus, CD34(+) AML and ALL cells can be induced to differentiate into leukemic DC with morphologic, phenotypic, and functional similarities to normal DC. (+info)
Distinct expression patterns of the p53-homologue p73 in malignant and normal hematopoiesis assessed by a novel real-time reverse transcription-polymerase chain reaction assay and protein analysis.
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The role of the recently identified first p53-homologue, p73, in neoplastic transformation is unknown. To elucidate p73 gene expression in hematopoiesis, we investigated samples from chronic myeloid leukemia (CML) and acute myeloid leukemia patients, leukemia cell lines, as well as mature and immature normal hematopoietic cells by real-time quantitative RT-PCR and Western blot analysis. We found a distinct p73 expression profile with highest p73 mRNA transcript levels in hematopoietic malignancies such as CML blast crisis and acute myelogenous leukemia versus CML chronic phase and normal controls. Mono- and biallelic p73 expression was found in both normal and malignant hematopoiesis. p73 protein was expressed at various levels in leukemia samples and cell lines but could not be detected in any normal controls tested. Our results point to a distinct yet undefined role of p73 in the pathogenesis of myeloid neoplasms. (+info)