Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD68 molecules are heavily glycosylated lysosomal membrane constituents of unknown function with strong expression in monocytes and macrophages. Using flow cytometry, we quantified expression levels of CD68 molecules in normal and malignant haemopoietic cells. CD68 molecules are intensely expressed in the cytoplasm and weakly on the surface of mature CD14+ monocytes. CD68 expression seems to start very early during granulomonopoietic differentiation. Virtually all myeloperoxidase (MPO)+ bone marrow cells coexpress CD68 and similar proportions of CD34+ progenitor cells weakly express CD68 or MPO molecules. During further differentiation, CD68 expression is strongly up-regulated in early MPO+ precursor cells which lack lactoferrin (LF) and CD14 molecules. Compared to these, more mature MPO+LF+ bone marrow and peripheral blood granulocytes express considerable lower levels of CD68. In-line with this broad expression, all investigated acute myeloid leukaemia (AML) cases, classified as FAB M1-M5, were CD68 positive, and compared to normal CD34+ bone marrow cells. CD34+ AML blast cells expressed increased levels. CD68 expression is, however, not restricted to cells of myeloid origin, because a subset (40 +/- 15%, n = 6) of CD19+ peripheral blood B-lymphocytes and 50% of B-ALL are also weakly positive. In contrast, normal CD3+ lymphocytes lack (< 3%, n = 6) CD68 and only low proportions (6 +/- 3%, n = 6) of CD56+ NK cells are CD68+. Also, all investigated T-ALL cases (n = 6) lacked CD68.
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PMID:Flow cytometric analysis of intracellular CD68 molecule expression in normal and malignant haemopoiesis. 766 55

The t(1;19)(q23;p13) translocation occurs commonly in B-lineage ALL. Previous reports have demonstrated a predominance of cases with expression of cytoplasmic Ig mu (C mu+), and FAB L1/L2 phenotype, a poor prognosis and expression of a fusion transcript involving the E2A and PBX1 genes in C mu+ but not in C mu- cases. Of 38 patients with karyotypically proven t(1;19) (q23;p13) leukaemias, we extensively analysed 18 patients with acute leukaemia including 16 B-lineage ALLs, one T-ALL and one AML M4. The AML was associated with a classic E2A-PBX1 fusion transcript and may represent the human counterpart of the AMLs induced by E2A-PBX1 retroviral infection of murine marrow progenitors. The T-ALL was E2A-PBX1 negative and neither the E2A nor the LYL-1 genes, both situated at chromosome 19 p13, were rearranged. Of the 16 B-lineage ALLs, four had cytological features resembling an 'L3-like' phenotype classically associated with Burkitt's lymphoma, two at diagnosis and relapse and two exclusively at relapse. E2A-PBX1 fusion transcripts were detected by RT-PCR in all 13 C mu+ patients and in 2/3 C mu- cases. The 'L3-like' phenotype did not correlate with a particular stage of maturation arrest (one sIg+, one C mu+, one C mu-) or type of E2A-PBX1 transcript, but was associated in all cases with a trisomy 8. Translocation, rearrangement, amplification or over-expression of the c-myc gene was not observed in these cases, demonstrating that the apparent association with trisomy 8 is not due to deregulation of this gene. We therefore show that the E2A-PBX1 transcript, although occurring predominantly in C mu+ pre-B ALL, also occurs in C mu- early pre-B ALL, sIg+ B-ALL and even in AML. These results suggest that the stage of maturation arrest, and indirectly the prognosis, are not solely due to the type of fusion transcript associated with the t(1;19).
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PMID:Heterogeneity of t(1;19)(q23;p13) acute leukaemias. French Haematological Cytology Group. 773 49

ALL is characterized by small to medium sized leukaemic blasts with a rather low grade of cell-to-cell variability. The nucleocytoplasmic ratio is high with just a small cytoplasmic rim in many cases. The cytoplasm tends to be moderately basophilic. Usually, though not in each instance, it is agranular and free of vacuoles. The chromatin is more condensed than in AML and the nucleoli tend to be indistinct. The FAB classification of haematological malignancies separates ALL into three categories: ALL L1, L2, and L3. However, just the identification of the L3 variant is of major importance. The L3 cells are medium sized to large and are characterized by intensely basophilic and moderately abundant cytoplasm with prominent cytoplasmic vacuolation in the bone marrow but not necessarily in the peripheral blood. According to our experience there is a high but not universal correlation of the L3 phenotype as defined by morphology with the immunologically defined B-ALL with surface expression of immunoglobulins. Until recently, acute leukaemias proving negative for all cytochemical tests especially for the PAS reaction and for the focal type of acid phosphatase, were termed 'acute undifferentiated leukaemia' (AUL). However, this morphological/cytochemical diagnosis may be confused with the immunological diagnosis of unclassifiable leukaemia. Since almost any of these cases can be recognized as ALL or AML by immunology, the term AUL should be reserved for cases which can be classified neither by morphology/cytochemistry nor by immunology. The morphological and cytochemical distinction of ALL from poorly differentiated AML remains a problem, especially if the FAB criteria for distinguishing ALL from AML by cytochemistry (3% of the blasts positive for peroxidase) are applied rigidly. A small but significant percentage of poorly differentiated leukaemias have less than 3% of the blasts positive for peroxidase and the myeloid nature of the leukaemia can be identified by cytochemistry. The absence of blasts being positive for peroxidase is no reliable indicator for the lymphatic nature of a leukaemia, even if the PAS reaction is typical for ALL. The morphological diagnosis of ALL needs confirmation by immunology in each instance.
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PMID:Morphology and cytochemistry of acute lymphoblastic leukaemia. 780 1

The p16 protein is a cyclin inhibitor encoded by a gene located in 9p21, which may have antioncogenic properties, and is inactivated by homozygous p16 gene deletion or, less often, point mutation in several types of solid tumors often associated to cytogenetic evidence of 9p21 deletion. We looked for homozygous deletion and point mutation of the p16 gene in acute lymphoblastic leukemia (ALL), where 9p21 deletion or rearrangement are also nonrandom cytogenetic findings. Other hematologic malignancies including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), and myeloma were also studied. Homozygous deletion of the p16 gene was seen in 9 of the 63 (14%) ALL analyzed, including 6/39 precursor B-ALL, 3/12 T-ALL, and 0/12 Burkitt's ALL. Three of the 7 ALL with 9p rearrangement (including 3 of the 5 patients where this rearrangement was clearly associated to 9p21 monosomy) had homozygous deletion compared to 5 of the 55 patients with normal 9p (the last patient with homozygous deletion was not successfully karyotyped). Single stranded conformation polymorphism analysis of exons 1 and 2 of the p16 gene was performed in 88 cases of ALL, including the 63 patients analyzed by Southern blot. Twenty-six of the cases had 9p rearrangement, associated to 9p21 monosomy in at least 12 cases. A missense point mutation, at codon 49 (nucleotide 164), was seen in only 1 of the 88 patients. No homozygous deletion and no point mutation of the p16 gene was seen in AML, MDS, CLL, and myeloma. Homozygous deletion of interferon alpha genes (situated close to p16 gene in 9p21) was seen in only 3 of the 9 ALL patients with p16 gene homozygous deletion, and none of the ALL without p16 gene homozygous deletion. Our findings suggest that homozygous deletion of the p16 gene is seen in about 15% of ALL cases, is not restricted to cases with cytogenetically detectable 9p deletion, and could have a pathogenetic role in this malignancy. On the other hand, p16 point mutations are very rare in ALL, and we found no p16 homozygous deletions or mutations in the other hematologic malignancies studied.
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PMID:p16 gene homozygous deletions in acute lymphoblastic leukemia. 783 69

The purpose of our investigations was to measure P-glycoprotein (P-170) activity in blast cells of 35 adults with acute myeloid leukemia (AML), and 24 children and adults with acute lymphoblastic leukemia (ALL) at time of diagnosis. Studies were based on a flow cytometric assay that detects efflux of the fluorescent dye rhodamine 123 (Rh123), which is transported from the cell by the P-170 pump. Dual-fluorescence staining with Rh123 and phycoerythrin-labeled monoclonal antibodies allowed selective measurement of Rh123 efflux in blast cells. Samples were scored positive when the fraction of blast cells showing Rh123 efflux exceeded 10% after a 120-min incubation. Activity of P-170 was observed in 19 (54%) of the 35 AML cases and was completely blocked in the presence of multidrug resistance inhibitors. Efflux activity was significantly higher in CD34-positive AML samples (p < 0.02). All AML patients with the FAB-subtype M5 (n = 5) lacked Rh123 pumping activity (p < 0.03). The complete remission rate in response to induction chemotherapy was significantly higher for Rh123-negative (11/13, 85%) than for Rh 123-positive AML patients (4/15, 27%) (p < 0.007). At a median follow-up of 9 months overall survival was significantly shorter for Rh123-positive than for Rh123-negative patients (p < 0.05). In contrast to AML, we could detect Rh123 efflux in only two (8%) out of 24 ALL cases. The immunological subtypes of these two positive cases was of B-ALL and pre-T-ALL. Bone marrow cryostat sections from 13 AML and five ALL patients were further analyzed for staining with monoclonal antibodies MM4.17 and JSB1. Ten of 13 AML and two of five ALL cases expressed the MDR protein. Our results indicate that there is a rather low frequency of P-170 pumping activity in ALL compared with AML. Further, functional activity of P-170 contributes to chemoresistance in de novo AML.
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PMID:Low frequency of activity of P-glycoprotein (P-170) in acute lymphoblastic leukemia compared to acute myeloid leukemia. 786 74

Plasma levels of soluble interleukin-2 receptor (sIL-2R), soluble CD8 (sCD8) and soluble intercellular adhesion molecule 1 (sICAM-1) were determined by ELISA assays in about 100 patients with hairy cell leukemia (HCL), acute myelomonocytic leukemia (AMMoL), acute myelocytic leukemia (AML), chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), acute lymphoblastic leukemia (ALL), adult T-cell leukemia (ATL), and mycosis fungoides (MF). Additionally, cultured AML, ALL, and CLL cells grown with and without 12-0-tetra-decanoyl-phorbol-13-acetate (TPA) were tested for IL-2R (CD25) expression by indirect immunofluorescence. Supernatants of these cultures were also tested for sIL-2R by ELISA. Elevated sIL-2R levels were found in HCL patients at initial diagnosis and relapse, in AMMoL, in AML, in the accelerated and non-accelerated phases of B-CLL, in PLL, in non-T/non-B ALL, in B-ALL in mixed lineage ALL, in T-CLL, in T-ALL, and in active MF. Reduced levels of sIL-2R were encountered in HCL patients in remission, in pre-T-ALL, and in MF patients in remission. Also, in non-accelerated CLL sIL-2R levels were less elevated than in later stages of the disease. In T-CLL, sIL-2R was only slightly elevated. Thus, we believe sIL-2R could prove to be a useful marker of disease stage, subtype, and prognosis in several hematologic malignancies. The cultures with and without TPA suggested that the undetermined source of sIL-2R in HCL, ALL and AML could indeed be the malignant cells but perhaps not so in the case of B-CLL. Plasma sCD8 was found to be below normal control levels in HCL, and lowest in relapsing cases. In addition, sCD8 levels were below normal in pre-T-ALL, and in MF. Levels in the non-accelerated phase of B-CLL approximated those of controls. Elevated levels of sCD8 were observed in AML, AMMoL, accelerated stage B-CLL, PLL, non-T/non-B ALL, B-ALL, mixed lineage ALL, T-ALL, T-CLL, and ATL. Thus, in a few instances, sCD8 may also correlate with disease subtype, as well as stage. Although sICAM-1 levels were elevated in all leukemias, its levels in CLL did not appear to be related to disease activity. Whether this is true or not for other leukemias would require additional work on sICAM-1 levels and its relationship to disease activity and prognosis.
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PMID:Soluble interleukin-2 receptor, soluble CD8 and soluble intercellular adhesion molecule-1 levels in hematologic malignancies. 790 67

The value of immunohistochemical staining in the subtyping of acute leukemia was investigated on 36 routinely processed (formalin-fixed and paraffin-embedded) trephine biopsy specimens from the iliac crest containing diffuse infiltrates of acute myelogenous leukemia (AML; n = 23) and acute lymphoblastic leukemia (ALL; n = 13). These were stained with a broad panel of antibodies (n = 23) against various leukocyte antigens, among them 11 macrophage-associated antibodies (MAAs): Ki-M1p, MAC387, HAM56, LN5, KP1 (CD68), PG-M1 (CD68), Ki-M4p, DAKO-DRC (CD35), and antibodies against lysozyme, alpha 1-antichymotrypsin, and S100 protein. The French-American-British (FAB) classification subtypes of the AML cases, as determined by enzyme-cytochemical and/or immunocytological investigation of bone marrow smears, were as follows: M1 = 6, M2 = 5, M4 = 7, M5 = 3, and AML (not classified) = 2. The 13 cases of ALL were classified as follows: c-ALL (pre-B-ALL) = 7, B-ALL = 3, T-ALL = 2, and ALL (not classified) = 1. All the MAAs except LN5, Ki-M4p, and DAKO-DRC stained blast cells in AML. However, the number of stained blast cells varied considerably within and between the individual subtypes (M4/5 > M2/1). Using Fisher's exact test a significant difference in frequency of blast cell staining between AML and ALL was found for four MAAs (anti-lysozyme, MAC387, Ki-M1p, and KP1) and two of the three myeloid cell markers applied (Ki-My2p and anti-neutrophil elastase). Of these six antibodies, the combination of anti-lysozyme and KP1 can be recommended for use in routine diagnostics for the differentiation of AML from ALL on the basis of immunohistochemical staining because both of these antibodies were found to stain a relatively large percentage of cases of AML but none of ALL. However, none of the MAAs were found to discriminate reliably between the FAB M4/5 and M1/2 subtypes of AML.
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PMID:Assessment of the value of immunohistochemistry in the subtyping of acute leukemia on routinely processed bone marrow biopsy specimens with particular reference to macrophage-associated antibodies. 805 22

Twenty-two patients with high risk hematologic malignancies (13 c-ALL, two B-ALL/NHL, four T-ALL, two AML M2, one pre-pre B-ALL) entered a phase I/II trial with cyclic administration of low dose natural interleukin-2/recombinant interferon-gamma (nIL-2/rIFN-gamma) following autologous bone marrow transplantation (ABMT), in order to induce a cytotoxic antileukemic effect. Eighteen patients subsequently relapsed, corresponding to a Kaplan-Meier estimate of disease-free survival (DFS) of 18%. Compared with a historical group of autologous bone marrow recipients who have not received immunotherapy, there is no significant difference according to DFS. Immunophenotyping of peripheral lymphocytes at the onset and end of therapy cycles revealed the most significant mean increase among the NK cell population (262/microliters +/- 51 vs. 354/microliters +/- 36, p = 0.004). However, even CD3 positive T cells rose significantly (591/microliters vs. 689/microliters, p = 0.04). In vitro NK cell activity tested against the NK sensitive myeloid leukemic cell line K562, and LAK cell activity tested against the LAK sensitive Burkitt lymphoma cell line Raji, was only low. An additional in vitro stimulus with nIL2, however, led to a therapy-dependent increase of cytotoxicity which was significant against Raji cells (25% +/- 4 vs. 41% +/- 5, p = 0.0124) indicating that low dose nIL2/rIFN-gamma enhances precursors of potentially cytotoxic cells in vivo.
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PMID:Low-dose natural interleukin-2 and recombinant interferon-gamma following autologous bone marrow grafts in pediatric patients with high-risk acute leukemia. 818 41

The culture supernatants from 43 human cell lines obtained during log phase and from purified normal peripheral blood B-lymphocytes cultured at 10(6) cells ml-1 for 48 h in RPMI 1640-5% fetal calf serum were examined for interleukin-8 (IL-8) using Elisa kits. Constitutive IL-8 production was found for 14/15 B-cell lines (5 derived from normal persons and 2 from AML patients, 1 pre-B-ALL, 2 CLL with trisomy 12, 2 HTLV-I+, 1 HTLV-II+, 1/2 Burkitt lymphoma), 4/16 T-cell lines (3/6 HTLV-I+, 1 HTLV-II+, 0/9 T-ALL), myeloid line HL-60, monocytoid line U937, 3/3 ovarian carcinoma, 1/1 endometriosis, 2/2 normal fibroblast, 0/2 C-ALL, 0/1 pre-erythroid line K562, as well as for normal B-lymphocytes. Later, cells examined by indirect immunofluorescence using IL-8 antibodies gave a positive reaction. DNA from 4 IL-8 producing and 3 non-producing cell lines, when probed with IL-8 cDNA gave the same 3.5 kb EcoRI fragment indicating similarities of the IL-8 gene in these cells. Two B-cell lines examined showed the expression of 1.8 kb IL-8 mRNA. These results indicate IL-8 production by a greater variety of cells than previously believed which open possibilities for new IL-8-mediated immune functions by such cells as B-cells.
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PMID:Constitutive production of interleukin-8 (IL-8) by normal and malignant human B-cells and other cell types. 824 10

A number of methods are available for classifying lymphoid and myeloid leukemias in peripheral blood and bone marrow. However, in clinical diagnosis an initial and particularly important step is morphologic analysis. All the cells in this investigation were classified by two hematologic experts. In most cases, immunophenotyping and immunocytochemical analyses were performed. Routinely prepared Romanowsky-Giemsa-stained peripheral blood smears (approximately 23,000 cells) were scanned by a high-resolution color TV/microscope system and analyzed by color and texture algorithms. In addition to blast cells, lymphocytes and monocytes exhibited a leukemia-associated change in morphology. The calculated texture and color features were most significant for the subtyping performed by the statistical program. With multivariate statistical analysis, seven mathematical subtypes of lymphocytes and five of monocytes could be found over all the specimens. Acute myeloblastic leukemia (AML, M1-M2), acute myelomonocytic leukemia (AMMOL, M4) and acute monocytic leukemia (AMOL, M5) could be differentiated by their distributions of monocyte subtypes. However, this was impossible for the lymphocyte subtypes. Acute lymphoblastic leukemias (B-ALL and T-ALL) were discernible with the aid of lymphocyte subtypes and acute myeloid conditions from viral infections, such as with the Epstein-Barr virus. The method increased the relevance of image processing in clinical diagnosis of acute leukemias and showed that the "normal" cell populations were not really normal in malignant leukemias.
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PMID:Malignancy-associated changes in monocytes and lymphocytes in acute leukemias measured by high-resolution image processing. 829 27


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