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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have used the 7AAD/PY method to analyze the cell cycle status of normal human bone marrow hematopoiesis, and found that the cell kinetics differed. There were cells with relatively low levels of RNA in the S-phase (Type I) and a high level in the S-phase (Type 11). T-cells, B-cells, nucleated red cells and CD34+/CD19+ early B-cells in bone marrow were Type I, whereas myelomonocytic subset and CD34+/CD33-dim+ common myeloid cells were Type II. AC133+/CD38-dim cells, which were thought to be lineage-marker negative hematopoietic stem cells, had intermediate amounts of RNA in the S-phase between Type I and II (Type 0). Seventy-four cases of acute leukemia were also analyzed. Most of the T- and B-ALL cases were found to be Type I, most of the ANLL cases were Type II, and there were 10 cases that were Type 0. These findings yielded fundamental information about normal hematopoiesis and acute leukemia.
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PMID:Cell kinetic study of normal human bone marrow hematopoiesis and acute leukemia using 7AAD/PY. 1068 Jul 1

Among a variety of immunodeficient mouse strains the non-obese diabetic (NOD)/LtSz scid/scid strain appears to be most useful in allowing the engraftment of human AML. However, the large variability in ability to engraft and the levels of engraftment reached have not been explained. To address these issues we have investigated the NOD/SCID repopulating ability of 27 newly diagnosed AML samples. Patients were selected for the absence of internal tandem duplications in the Flt3 gene as we previously reported this mutation to be associated with an enhanced engraftment potential in this model. We observed that secondary AML (n = 6) had a significantly increased level of engraftment when compared to primary AML (n = 21, median levels 73.3% for secondary AML vs 8.94% for primary AML, P = 0.01). Within the primary AML, a significantly higher engraftment was observed in the FAB class M0 than in FAB classes M2, M4 and M5. Within primary AML, samples of patients who failed to respond to the initial therapy gave rise to a higher level of engraftment than samples of patients who did respond to therapy. A similar observation of an increased engraftment correlating with a poorer patient prognosis could be made when applying cytogenetic risk stratification. However, within the primary AML the most important clinical parameter correlating with the level of engraftment appeared to be the patient's WBC count at diagnosis (P = 0.0000). Covariate analysis with the WBC count as a covariate could also fully explain the differences observed in the cytogenetic risk groups, or on the basis of the initial therapy response. Although large differences could be observed, the ability to engraft the NOD/SCID mice was not linked to either the autonomous or cytokine-induced proliferation in vitro. As the leukemic cobblestone area-forming cell frequencies also revealed no correlation with repopulation in the NOD/SCID model, we consider it very likely that the level of engraftment reflects the in vivo proliferative ability of the AML samples assayed rather than the number of leukemia-initiating cells infused into the NOD/SCID mice. Phenotypic analysis based on the expression of CD33, CD34 and CD38 before and after passage in NOD/SCID showed that in 10 out of 16 samples investigated phenotypes were different. In summary, in addition to the Flt3 internal tandem duplications we have identified a series of clinical parameters that determine the NOD/SCID repopulating ability of AML samples, whilst our data strongly suggest that AML in NOD/SCID does not reflect the leukemic process in the patient.
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PMID:Identification of variables determining the engraftment potential of human acute myeloid leukemia in the immunodeficient NOD/SCID human chimera model. 1080 22

From a cohort of 220 adults with newly diagnosed acute myeloid leukemia (AML), 8 (3.6%) exhibited a rare variant of aberrant membrane phenotype. It was characterized with typical myeloid morphologic and cytochemical patterns and absence of myeloid associated antigens (CD13, CD33, CD14, glycophorin A, CD61). According to the French-American-British criteria, disease in 5 patients was classified as M1 and in 3 patients as M2. CD34, CD38, HLA-DR, and CD45 were strongly expressed in 4 of 5, 3 of 3, 8 of 8, and 3 of 3 analyzed cases, respectively. CD7 antigen was strongly expressed in 4 of 6 patients. Except for predominance of male sex and high frequency of CD7 antigen expression, no other remarkable clinical or biologic characteristics were noted. Detected variant of AML with the unusual membrane phenotype (CD34+, HLA-DR-positive, CD38+, CD45+, CD7+) might represent an example of extreme asynchrony in sequences of morphologic and immunologic maturation or abnormal epitope expression on leukemic cell membrane molecules CD13 and CD33. Although the clinical significance of this AML variant is unclear, the existence of such cases demonstrates the continued need for simultaneous cytochemical and immunologic studies in the evaluation of acute leukemias.
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PMID:Characterization of CD13 and CD33 surface antigen-negative acute myeloid leukemia. 1176 84

The destruction of cells capable of initiating and maintaining leukemia challenges the treatment of human acute myeloid leukemia. Recently, CD34+/CD38- leukemia progenitors have been defined as new leukemia-initiating cells less mature than colony-forming cells. Here we show that CD34+/CD38- leukemia precursors have reduced in vitro sensitivity to daunorubicin, a major drug used in leukemia treatment, in comparison with the CD34+/CD38+ counterpart, and increased expression of multidrug resistance genes (mrp/lrp). These precursors show lower expression of Fas/Fas-L and Fas-induced apoptosis than CD34+/CD38+ blasts. Moreover, the CD34+/CD38- leukemic subpopulation induces a weaker mixed leukocyte reaction of responding T-lymphocytes than the CD34+/CD38+ leukemic counterpart, either in a MHC-unmatched or MHC-matched settings. This weaker immunogenicity could be linked to lower expression on CD34+/CD38- leukemia precursors of major immune response molecules (MHC-DR, LFA-3, B7-1, or B7-2) than CD34+/CD38+ leukemic cells. Nonetheless, the susceptibility of the immature CD38- precursors to cytotoxicity was not different from the sensitivity of the CD38+ counterpart. Finally, CD34+/CD38- leukemia precursors, in contrast with CD38+ precursors, failed, under appropriate conditions, to differentiate into dendritic cells, a central step for antigen recognition. This is to our knowledge the first demonstration that the very immature phenotype of CD34+/CD38- leukemic progenitors confers both chemotherapy resistance and decreased capacities to induce an immune response. Because the susceptibility of the immature leukemia cells as cytotoxic targets is maintained, our data underline the importance of improving the initial steps of leukemia recognition, more particularly by defining optimal conditions of dendritic cell transformation of the very immature hematopoietic precursors.
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PMID:Human acute myeloid leukemia CD34+/CD38- progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities. 1096 85

We reported previously that treatment with all-trans retinoic acid (ATRA) and granulocyte macrophage colony-stimulating factor (GM-CSF) induces differentiation of human myeloblastic leukemia ML-1 cells to granulocytes, whereas treatment with ATRA alone induces practically no differentiation of these cells. To investigate the mechanism of the synergistic effect of these factors, we examined the effect of GM-CSF on retinoic acid receptors (RARs) and retinoid X receptors (RXRs) in ML-1 cells. We reveal that GM-CSF induces the expression of RAR alpha mRNA and protein and stimulates the binding of nuclear proteins to direct repeat 5, a consensus sequence with high affinity for RAR-RXR heterodimers. Furthermore, expression of CD38 mRNA mediated through RAR alpha is induced synergistically by treatment with ATRA + GM-CSF. These results suggest that GM-CSF stimulates transcriptional activity mediated via RAR alpha in ML-1 cells. The induction of RAR alpha by GM-CSF may therefore be a mechanism for stimulation by GM-CSF. The induction of RAR alpha by GM-CSF was also detected in other myeloid leukemia cell lines (THP-1 and KG-1) that showed a synergistic effect similar to that seen in ML-1 cells in response to ATRA + GM-CSF. We also found that GM-CSF induced the expression of RAR alpha in blood cells obtained from patients with acute myeloid leukemia. This activity of GM-CSF may serve as a useful adjunct to differentiation therapy for retinoic acid-nonresponsive leukemias.
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PMID:Induction of retinoic acid receptor-alpha by granulocyte macrophage colony-stimulating factor in human myeloid leukemia cell lines. 1096 5

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis and frequent progression to acute myeloid leukemia. Within MDS, 5q- syndrome constitutes a distinct clinical entity characterized by an isolated deletion of the long arm of chromosome 5 (5q-), a relatively good prognosis, and infrequent transformation to acute leukemia. The cell of origin in 5q- syndrome as well as in other 5q-deleted MDS patients has not been established, but evidence for involvement of multiple myeloid (but not lymphoid) lineages has suggested that a myeloid-restricted progenitor rather than a pluripotent (lympho-myeloid) stem cell might be the primary target in most patients. Although in 9 patients no evidence of peripheral blood T-cell and only 1 case of B-cell involvement was found, the data herein support that 5q deletions occur in hematopoietic stem cells (HSCs) with a combined lympho-myeloid potential. First, in all investigated patients a minimum of 94% of cells in the minor CD34(+)CD38(-) HSC compartment were 5q deleted as determined by fluorescence in situ hybridization. Second, in 3 of 5 patients 5q aberrations were detected in a large fraction (25% to 90%) of purified CD34(+)CD19(+) pro-B cells. Furthermore, extensive functional characterization with regard to responsiveness to early-acting cytokines, long-term culture-initiating cells, and nonobese diabetic/severe combined immunodeficiency repopulating cells supported that MDS HSCs in 5q-deleted patients are CD34(+)CD38(-), but inefficient at reconstituting hematopoiesis.
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PMID:Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level. 1097 41

Recent studies suggest that the population of malignant cells found in human acute myelogenous leukemia (AML) arises from a rare population of leukemic stem cells (LSCs). LSCs have been documented for nearly all AML subtypes and have been phenotypically described as CD34+/CD38- or CD34+/HLA-DR-. Given the potentially critical role of these primitive cells in perpetuating leukemic disease, we sought to further investigate their molecular and cellular characteristics. Flow cytometric studies using primary AML tissue showed that the interleukin-3 receptor alpha chain (IL-3Ralpha or CD123) was strongly expressed in CD34+/CD38- cells (98 +/- 2% positive) from 16 of 18 primary specimens. Conversely, normal bone marrow derived CD34+/CD38- cells showed virtually no detectable expression of the CD123 antigen. To assess the functional role of IL-3Ralpha positive cells, purified CD34+/CD123+ leukemia cells were transplanted into immune deficient NOD/SCID mice. These experiments showed that CD123+ cells were competent to establish and maintain leukemic populations in vivo. To begin to elucidate a biological role for CD123 in leukemia, primary AML samples were analyzed with respect to signal transduction activity in the MAPK, Akt, and Stat5 pathways. Phosphorylation was not detected in response to IL-3 stimulation, thereby suggesting CD123 is not active in conventional IL-3-mediated signaling. Collectively, these data indicate that CD123 represents a unique marker for primitive leukemic stem cells. Given the strong expression of this receptor on LSCs, we propose that targeting of CD123 may be a promising strategy for the preferential ablation of AML cells.
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PMID:The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. 1102 53

We searched for trisomy 11 in acute myelogenous leukemia (AML) patients using the Japan Adult Leukemia Study Group (JALSG) AML-92 and -95 databases to clarify the clinical and hematologic features of a rare numerical chromosome abnormality. Among the sequentially registered patients of JALSG AML-92 (655 patients) and JALSG AML-95 (531 patients), chromosome findings were obtained for 1074 patients (90.6%); we found 5 patients with trisomy 11 as the sole abnormality. The patients were 4 women and 1 man with trisomy 11 AML, all aged more than 45 years (median, 52 years), with 4 M1 morphologies and 1 M2. No patients manifested hepatosplenomegaly or lymph node enlargement, and no central nervous system leukemia or extramedullary lesions were detectable. All showed positivity for CD13 (5/5), CD33 (5/5), CD34 (3/3), CD38 (2/2), and HLA-DR (5/5). Except for 1 patient, all achieved complete remission after 1 course of induction chemotherapy, but 2 relapsed after discontinuation of chemotherapy. A third case of relapse occurred during intensification of chemotherapy, and the patient underwent allogenic bone marrow transplantation but died from interstitial pneumonia.
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PMID:Trisomy 11 acute myeloid leukemia: 5 additional cases from the Japan Adult Leukemia Study Group AML-92 and AML-95 databases. 1119 13

Previous studies indicate that human acute myelogenous leukemia (AML) arises from a rare population of leukemic stem cells. Cells of this nature can initiate and maintain leukemic cell growth in both long-term cultures and nonobese diabetic/severe combined immune-deficient mice. To characterize the biology of primitive AML cells, gene expression screens were performed with 7 primary AML and 3 normal specimens. For each sample, stem cell populations (CD34(+)/CD38(-)) were isolated and used to synthesize radiolabeled complementary DNA (cDNA). AML vs normal probes were then hybridized to cDNA arrays containing genes related to cancer and apoptosis. Of approximately 1400 genes analyzed, 2 tumor-suppressor genes were identified that were overexpressed in all 7 of the AML CD34(+)/CD38(-) cell populations: death-associated protein kinase and interferon regulatory factor 1. Expression of each gene was confirmed by reverse-transcription polymerase chain reaction and immunoblot analysis. It is proposed that tumor-suppressor proteins play a role in the biology of primitive AML cells. (Blood. 2001;97:2177-2179)
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PMID:Expression of tumor-suppressor genes interferon regulatory factor 1 and death-associated protein kinase in primitive acute myelogenous leukemia cells. 1126 90

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow disorder with varying cytopenias and a strong predilection to myelodysplastic syndrome (MDS) and acute myeloid leukemia. Previously, it was found that the percentage of CD34(+) cells in bone marrow and the in vitro colony formation from CD34(+) cells of patients with SDS were markedly reduced. For these reasons, and because apoptosis is central in the pathogenesis of bone marrow dysfunction in MDS, this study was initiated to delineate the role of apoptosis in the pathogenesis of the marrow failure. Eleven children with SDS were studied. Compared to normal controls, patients' marrow mononuclear cells plated in clonogenic cultures showed a significantly higher tendency to undergo apoptosis. The defect in SDS was found in patients with and without MDS. Patients showed a more prominent decrease in colony formation and increased apoptosis after preincubation with activating anti-Fas antibody. Fas expression on marrow cells from patients was significantly higher than from normal controls. The difference between patients and controls for Fas expression was also significant for the following cell fraction subpopulations: CD34(-)/CD38(-), CD34(-)/CD38(+), and CD34(+). In conclusion, SDS hematopoietic progenitors are intrinsically flawed and have faulty proliferative properties and increased apoptosis. Bone marrow failure in SDS appears mediated by increased apoptosis as the central pathogenetic mechanism. This increased propensity for apoptosis is linked to increased expression of the Fas antigen and to hyperactivation of the Fas signaling pathway.
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PMID:Shwachman-Diamond syndrome marrow cells show abnormally increased apoptosis mediated through the Fas pathway. 1134 25


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