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PubMed1998

Stem cell factor enhances the adhesion of AML cells to fibronectin and augments fibronectin-mediated anti-apoptotic and proliferative signals.

Acute myeloid leukaemia (AML) cells express the SCF receptor c-kit (CD117) on their cell surface and demonstrate enhanced adhesion to fibronectin (FN) following exposure to stem cell factor (SCF). Increased adhesion occurs within 5 min, is dose dependent, and persists beyond 2 h. Baseline and enhanced adhesion occur through the surface FN receptor very late antigen-5 (VLA-5, CD49e/CD29) which is expressed by AML cells. Unstimulated AML cells exposed to FN undergo less apoptosis than controls (inhibition 22.5 +/- 7.0%, P = 0.02, n = 8). Exposure to SCF alone without FN also inhibits AML cell apoptosis (by 19.0 +/- 7.7% compared to controls, P = 0.06, n = 8). Simultaneous exposure to SCF and FN increases the inhibition of AML cell apoptosis to 37.8 +/- 7.9% (P = 0.005 compared to control, P = 0.04 compared to FN alone, P = 0.06 compared to SCF alone) demonstrating that SCF not only enhances the propensity of AML cells to adhere to FN, but also results in an additive survival benefit following FN contact. Some but not all the reduction in apoptosis is mediated through VLA-5. The combination of SCF and FN also affects proliferation, resulting in a synergistic enhancement of AML cell proliferation in half the cases studied. When normal CD34+ human haemopoietic progenitors were studied, FN had little effect on their apoptosis and failed to enhance the anti-apoptotic effect of SCF. It did, however, synergise with SCF in promoting CD34+ cell proliferation. Exposure of AML cells to SCF and FN, both of which can be found in high concentration in the bone marrow stroma, inhibits apoptosis. Cytokines and extracellular matrix proteins augment each others' effects since SCF enhances adhesion to fibronectin, which in turn augments the survival signal delivered by the cytokine alone. Cytokine and adhesion receptors can combine to affect cell characteristics including proliferation and survival.

Acute Disease↗

PubMed1998

GM-CSF receptor targeted treatment of primary AML in SCID mice using Diphtheria toxin fused to huGM-CSF.

The severe combined immunodeficient (SCID) mouse model may be used to evaluate new approaches for the treatment of acute myeloid leukemia (AML). We have previously demonstrated the killing of SCID mouse leukemia initiating cells by in vitro incubation with human GM-CSF fused to Diphtheria toxin (DT-huGM-CSF). In this report, we show that in vivo treatment with DT-huGM-CSF eliminates AML growth in SCID mice. Seven cases of AML were studied. SCID mice were treated intraperitoneally with the maximally tolerated dose of 75 microg/kg/day for 7 days. Antileukemic efficacy was determined at days 40 and 80 after transplantation, by enumerating the percentages of human cells in SCID bone marrow using flow cytometry and short tandem repeat polymerase chain reaction (STR-PCR) analysis. Four out of seven AML cases were sensitive to in vivo treatment with DT-huGM-CSF at both evaluation time points. In three of these cases, elimination of human cells was demonstrated by flow cytometry and STR-PCR. One AML case showed moderate sensitivity for DT-huGM-CSF, and growth of the two remaining AML cases was not influenced by DT-huGM-CSF. Sensitivity was correlated with GM-CSFR expression. Our data show that DT-huGM-CSF can be used in vivo to reduce growth of AML and warrant further development of DT-huGM-CSF for the treatment of human AML.

Animals↗

PubMed2003

Synthetic triterpenoids activate a pathway for apoptosis in AML cells involving downregulation of FLIP and sensitization to TRAIL.

Acute myelogenous leukemia (AML) remains a deadly disease for most adult patients, due primarily to the emergence of chemoresistant cells. Defects in apoptosis pathways make important contributions to chemoresistance, suggesting a need to restore apoptosis sensitivity or to identify alternative pathways for apoptosis induction. Triterpenoids represent a class of naturally occurring and synthetic compounds with demonstrated antitumor activity, including 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its methyl ester (CDDO-m). We explored the effects of CDDO and CDDO-m in vitro on established AML cell lines (HL-60, U937, AML-2) and on freshly isolated AML blasts. CDDO and CDDO-m reduced the viability of all AML cell lines tested in a dose-dependent manner, with effective doses for killing 50% of cells (ED(50)) within 48 h of approximately 1 and 0.5 muM, respectively. CDDO or CDDO-m also induced substantial increases in cell death in five out of 10 samples of primary AML blasts. Cell death induced by CDDO and CDDO-m was attributed to apoptosis, based on characteristic cell morphology and evidence of caspase activation. Immunoblot analysis demonstrated proteolytic processing of caspase-3, -7, and -8, but not caspase-9, suggesting the involvement of the 'extrinsic' pathway, linked to apoptosis induction by TNF-family death receptors. Accordingly, CDDO and CDDO-m induced concentration-dependent reductions in the levels of FLIP protein, an endogenous antagonist of caspase-8, without altering the levels of several other apoptosis-relevant proteins. Reductions in FLIP were rapid, detectable within 3 h after exposure of AML cell lines to CDDO or CDDO-m. CDDO and CDDO-m also sensitized two of four leukemia lines to TRAIL, a TNF-family death ligand. The findings suggest that synthetic triterpenoids warrant further investigation in the treatment of AML, alone or in combination with TRAIL or other immune-based therapies.

Antineoplastic Agents↗

PubMedDate not supplied

[Incidence and prognostic significance of Auer rods in children with acute myeloid leukemia in the studies AML-BFM-78 and -83].

The prognostic significance of Auer rods in children with AML was investigated in 129 patients of the study AML-BFM-78 and 154 patients of the study AML-BFM-83. Auer rods were found in 68 patients (53%) in the study AML-BFM-78 and 69 patients (45%) in the study AML-BFM-83. The incidence was higher in the subtypes FAB M1 (61%) and M2 (75%) compared to the subtypes FAB M4 (44%) and M5 (5%). In both studies the remission rate was higher in Auer rod-positive patients. Moreover, in the study AML-BFM-83 patients with Auer rods had a significant longer remission duration: the probability of an event-free interval (EFI) of 5 years was 77% (SD 6%) in Auer rod-positive patients compared with 44% (SD 7%) in Auer rod-negative patients (p less than 0.01). In the study AML-BFM-78 no differences regarding remission duration between both groups were detected. Analysis of the individual FAB subtypes revealed a significant higher event-free survival rate (EFS) after 5 years in Auer rod-positive compared with 18% (SD 12%) in Auer rod-negative patients (p less than 0.0001). No prognostic significance of Auer rods in other subtypes could be detected. In the overall group of all patients absence of Auer rods was associated with the unfavourable parameters hyperleucocytosis (greater than or equal to 100 x 10(3)/microliters) and acute monocytic leukemia (FAB M5) (p less than 0.01, p less than 0.001, respectively). The multivariate analysis in the study AML-BFM-83 showed that Auer rods were of prognostic significance independent from the initial leukocyte count and the FAB type M5.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1996

An AML-1 consensus sequence binds an osteoblast-specific complex and transcriptionally activates the osteocalcin gene.

Tissue and cell-type specific expression of the rat osteocalcin (rOC) gene involves the interplay of multiple transcriptional regulatory factors. In this report we demonstrate that AML-1 (acute myeloid leukemia-1), a DNA-binding protein whose genes are disrupted by chromosomal translocations in several human leukemias, interacts with a sequence essential for enhancing tissue-restricted expression of the rOC gene. Deletion analysis of rOC promoter-chloramphenicol acetyltransferase constructs demonstrates that an AML-1-binding sequence within the proximal promoter (-138 to -130 nt) contributes to 75% of the level of osteocalcin gene expression. The activation potential of the AML-1-binding sequence has been established by overexpressing AML-1 in osteoblastic as well as in nonosseous cell lines. Overexpression not only enhances rOC promoter activity in osteoblasts but also mediates OC promoter activity in a nonosseous human fibroblastic cell line. A probe containing this site forms a sequence specific protein-DNA complex with nuclear extracts from osteoblastic cells but not from nonosseous cells. Antisera supershift experiments indicate the presence of AML-1 and its partner protein core-binding factor beta in this osteoblast-restricted complex. Mutations of the critical AML-1-binding nucleotides abrogate formation of the complex and strongly diminish promoter activity. These results indicate that an AML-1 related protein is functional in cells of the osteoblastic lineage and that the AML-1-binding site is a regulatory element important for osteoblast-specific transcriptional activation of the rOC gene.

Animals↗

PubMed2003

Functional and immunophenotypic characteristics of isolated CD105(+) and fibroblast(+) stromal cells from AML: implications for their plasticity along endothelial lineage.

BACKGROUND: In vitro cultures of BM cells from newly diagnosed patients with AML displayed a defective BM stromal compartment, with a reduced number of fibroblast-colony-forming unit (CFU-F: 1 +/- 1.25 SD) and a decreased proliferative ability. The purposes of our study were: 1). to select BM mesenchymal stem cells (MSC) and BM-derived stromal cells (BMDSCs) from AML patients at diagnosis and from healthy subjects, using an immunomagnetic system and either anti-CD105 or anti-fibroblast MAbs; 2). to study the immunophenotypic and functional properties of freshly isolated and cultured mesenchymal cells; 3). to test the in vitro plasticity of the selected cells to differentiate towards an endothelial phenotype. METHODS: Fresh mononuclear cells obtained from BM of 20 patients newly diagnosed with AML and from eight healthy subjects were selected by using anti-fibroblast and anti-CD105 MAbs. Freshly isolated cells were analyzed, characterized by flow cytometry using a wide panel of MAbs and seeded in long-term culture medium to assess CFU-F formation. The level of confluence after 30 days and functional capacity in a long-term colony-forming cell culture (LTC-CFC) were tested. Furthermore, the cultured selected cell populations were assayed for their ability to differentiate into an endothelial-like cell phenotype with the addition of vascular endothelial growth factor (VEFG) and endothelial cell growth supplement (ECGS). RESULTS: In normal subjects the selection produced an increase of the CFU-F number of 2.6-fold with anti-fibroblast MAb and 2.7-fold with the anti-CD105 MAb. Anti-fibroblast and anti-CD105 MAb selection from AML BM cells resulted in a statistically significant greater count of CFU-F that was respectively 10.6-fold (P = 0.04) and 14.4-fold (P = 0.00001) higher in comparison with the unselected AML samples. Interestingly, in 80% of AML samples immunoselection was also able to restore the capacity of the CFU-F to proliferate and form confluent stromal layers. The isolation of those layers sustained the proliferation and differentiation of hematopoietic stem cells in the LTC-CFC. The phenotypic profile of cultured BMDSCs was different from that of the freshly isolated cells, and changed in relation to the culture conditions: CD105+ selected cells cultured with VEGF and ECGS expressed endothelial markers, a finding that suggests that this cell subpopulation may have the potential to differentiate toward an endothelial-like phenotype. DISCUSSION: We report that immunomagnetic selection represents a valid tool for the selection of BM mesenchymal cells in samples obtained from both healthy subjects and patients with AML. This technique was able to rescue two functional and immunophenotypic compartments related to two different selected populations. In particular, the CD105+ cells isolated in AML displayed, after stimulation with VEGF and ECGS, the ability to change towards an endothelial-like cell phenotype, thus revealing an unexpected plasticity. Both CD105+ and fibroblast+ cells once successfully isolated might represent sources of mesenchymal cells populations useful for in vitro investigations and, above all, as therapeutic devices.

Adult↗

PubMedDate not supplied

Gene therapy with B7.1 and GM-CSF vaccines in a murine AML model.

PURPOSE: Characterization of B7.1 and GM-CSF vaccines on the induction of anti-tumor immunity in a murine AML model. MATERIALS AND METHODS: Primary AML cells were retrovirally transduced with the murine costimulatory molecule B7.1, a natural ligand for the T-cell receptors CD28 and CTLA-4, or the cytokine GM-CSF. Mice were vaccinated with irradiated AML cells expressing B7.1 or GM-CSF before or after inoculation of wild type AML cells. RESULTS: Intravenous injection of irradiated B7.1 or GM-CSF expressing AML cells can provide long lasting systemic immunity against a subsequent challenge of wild type AML cells. Vaccination with irradiated B7.1 or GM-CSF expressing AML cells results in rejection of established leukemia when the vaccination occurs in the early stages of the disease. However, when the vaccines are administered > 2 weeks after leukemic inoculation, only mice which receive the GM-CSF vaccine are cured of leukemia. CONCLUSIONS: These results suggest that tumor burden and vaccine efficiency are most likely to be the limiting factors in the curative potential of tumor vaccines. Novel approaches such as this experiment could provide improved therapeutic outcomes in patients with AML and other cancers.

Animals↗

PubMed2006

Identification and molecular characterization of an N-Acetylmuraminidase, Aml, involved in Streptococcus mutans cell separation.

We previously demonstrated Streptococcus mutans produces two bacteriolytic enzymes of 100 kDa and 80 kDa (G. Yoshimura et al. Microbiol. Immunol. 48, 465-469, 2004). Here, we identified the protein sequence of these enzymes and found they come from a single gene product designated as automutanolysin (Aml). Aml has a modular design where the N-terminus contains five 13-amino-acid repeats and a C-terminal enzyme active domain. Aml selectively lyses S. mutans and S. sobrinus but no other oral streptococci. This suggests Aml possesses strong substrate specificity towards cariogenic bacteria present in the human oral cavity. Analysis of S. mutans peptidoglycan fragments released by Aml shows the enzyme is an N-acetylmuraminidase. We found Ca(2+) enhances the activity; and EGTA, EDTA and iodoacetic acid inhibit the activity. The optimum pH range for lytic activity was 6 to 7. Disruption of the aml gene in S. mutans results in the formation of a longer bacterial cell chain length that was dispersed by the addition of a low concentration of Aml. This suggests Aml is involved in S. mutans cell separation.

Amino Acid Sequence↗

PubMed1990

Relationship of thrombin generation to peripheral blast cell count in patients with acute myeloblastic leukemia (AML).

Disseminated intravascular coagulation (DIC) commonly occurs in patients with acute promyelocytic leukemia (APL, FAB-M3) but may also be seen in other subtypes of AML. DIC in patients with AML has been attributed to procoagulants released from granular fractions of leukemic blast cells. The present study was designed (i) to evaluate thrombin activity in patients with AML by measuring plasma levels of fibrinopeptide A (FPA) prior to chemotherapy, and (ii) to examine whether a relationship between FPA levels and the number of peripheral blast cells exists. Plasma levels of FPA were determined using a commercially available RIA kit. To remove fibrinogen and the majority of elastase-induced fibrinopeptides (A alpha 1-21) known to crossreact with the FPA (A alpha 1-16) antiserum used in this assay, plasma samples were treated with bentonite prior to further processing. The study was conducted on 5 patients with APL and on 22 patients with other subtypes of AML. Peripheral blast cell counts at initial diagnosis ranged from 2100 to 56,000/microliters in patients with APL and from 1900 to 151,000/microliters in patients with other AML subtypes. The mean (+/- 1 SEM) pretreatment plasma level of FPA was significantly higher (p = 0.021) in the 5 patients with APL (38.2 +/- 8.3 ng/ml) than in patients with other AML subtypes (8.1 +/- 0.7 ng/ml). No relationship was found between peripheral blast cell counts and the corresponding FPA levels in the total group of 27 patients. However, when considering the 5 patients with APL separately, a significant correlation was observed between peripheral blast cell number and FPA plasma levels (r = 0.88, p = 0.050). This study confirms that thrombin generation is considerably greater in patients with acute promyelocytic leukemia than in other subtypes of AML. We conclude that type and number of circulating blast cells and their related capacity to express procoagulant activities appear to be major determinants of excessive fibrinogen degradation in AML.

Blood Cells↗

PubMed2004

The peripheral benzodiazepine receptor ligand PK11195 overcomes different resistance mechanisms to sensitize AML cells to gemtuzumab ozogamicin.

The antibody-targeted therapeutic, gemtuzumab ozogamicin (GO, Mylotarg), is approved for treatment of relapsed acute myeloid leukemia (AML). We previously showed that AML blasts from GO refractory patients frequently express the drug transporters P-glycoprotein (Pgp) and/or multidrug resistance protein (MRP). We also previously reported that inhibition of drug transport by the Pgp modulator, cyclosporine A (CSA), can increase GO sensitivity in Pgp(+) AML cells and that the peripheral benzodiazepine receptor ligand, PK11195, sensitizes AML cells to standard chemotherapeutics both by inhibiting Pgp-mediated efflux and by promoting mitochondrial apoptosis. We now show that PK11195 also can overcome multiple resistance mechanisms to increase GO sensitivity in AML cells, including resistance associated with expression of drug transporters and/or antiapoptotic proteins. PK11195 substantially increases GO cytotoxicity in AML cells from many different cell lines and primary patient samples, often more effectively than CSA. We also show that PK11195 is nontoxic in NOD/SCID mice and can sensitize xenografted human AML cells to GO. Since PK11195 is well tolerated in humans as a single agent, its further study as a multifunctional chemosensitizer for anti-AML therapies, including GO-based therapies, is warranted.

Acute Disease↗

PubMed2005

Motility, proliferation, and egress to the circulation of human AML cells are elastase dependent in NOD/SCID chimeric mice.

The role of the proteolytic enzyme elastase in motility and proliferation of leukemic human acute myeloblastic leukemia (AML) cells is currently unknown. We report a correlation between abnormally high levels of elastase in the blood of AML patients and the number of leukemic blast cells in the circulation. In AML cells, we observed expression of cell-surface elastase, which was regulated by the chemokine stromal cell-derived factor-1 (SDF-1). In vitro inhibition of elastase prevented SDF-1-induced cell polarization, podia formation, and reduced migration of human AML cells as well as their adhesion. Elastase inhibition also significantly impaired in vivo homing of most human AML cells to the bone marrow (BM) of nonobese diabetic-severe combined immunodeficient (NOD/SCID)/beta-2 microglobulin knock-out (B2m null) mice that underwent transplantation. Moreover, in vitro proliferation of AML cells was elastase dependent. In contrast, treatment with elastase inhibitor enhanced the proliferation rate of human cord blood CD34+ cells, including primitive CD34+/CD38- cells, and their in vivo homing. Finally, NOD/SCID mice previously engrafted with human AML cells and treated with elastase inhibitor had significantly reduced egress of leukemic cells into the circulation. Taken together, our data demonstrate that human AML cells constitutively secrete and express SDF-1-dependent cell-surface elastase, which regulates their migration and proliferation.

Acute Disease↗

PubMed2005

Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+ AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance.

Approximately one third of acute myeloid leukemias (AMLs) are characterized by aberrant cytoplasmic localization of nucleophosmin (NPMc+ AML), consequent to mutations in the NPM putative nucleolar localization signal. These events are mutually exclusive with the major AML-associated chromosomal rearrangements, and are frequently associated with normal karyotype, FLT3 mutations, and multilineage involvement. We report the gene expression profiles of 78 de novo AMLs (72 with normal karyotype; 6 without major chromosomal abnormalities) that were characterized for the subcellular localization and mutation status of NPM. Unsupervised clustering clearly separated NPMc+ from NPMc- AMLs, regardless of the presence of FLT3 mutations or non-major chromosomal rearrangements, supporting the concept that NPMc+ AML represents a distinct entity. The molecular signature of NPMc+ AML includes up-regulation of several genes putatively involved in the maintenance of a stem-cell phenotype, suggesting that NPMc+ AML may derive from a multipotent hematopoietic progenitor.

Acute Disease↗

PubMed1999

Etoposide-induced DNA strand breaks in relation to p-glycoprotein and topoisomerase II protein expression in leukaemic cells from patients with AML and CLL.

Elevated expression of the membrane transporter p-glycoprotein (pgp) and impaired expression of the nuclear enzyme topoisomerase II (topo II) are well-known mechanisms for in vitro acquired drug resistance. The clinical relevance of topo II remains unclear, whereas a relationship between pgp levels and treatment results has been shown in acute myelogenous leukaemia (AML). We have investigated the relationships between the levels of topo II and pgp, and in vitro sensitivity to etoposide in mononuclear blood cells from 24 patients with AML, 16 with chronic lymphocytic leukaemia (CLL) and five healthy blood donors. Following incubation with etoposide, AML cells showed more DNA damage, determined by a DNA unwinding technique, than CLL cells (P = 0.001), whereas there was no difference in cellular etoposide accumulation. Pgp and topo IIbeta levels, determined by Western blot, showed a pronounced variation between patients, but no correlation with induced DNA damage, whereas topo IIalpha protein was undetectable. In the AML group, topo IIbeta expression correlated with pgp expression (rho = 0.7, P = 0.001, n = 24). The topo IIbeta expression was 147.4(+/-74.6)% in the pgp+ AML cells (n = 10), compared to 33.4(+/-27.8)% in pgp- AML cells (n = 14) (P = 0.0001). Our results show a previously unknown coexpression of topo IIbeta and pgp in AML, thereby suggesting that topo IIbeta is a potentially interesting resistance factor in AML.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1990

Mechanisms of growth factor expression in acute myeloid leukemia (AML).

To investigate possible mechanisms of growth factor expression in acute myeloid leukemia, genes for granulocyte macrophage colony-stimulating factor (GM-CSF) were analyzed by Southern blots in 20 patients, for M-CSF in 13, for interleukin-6 (IL-6) in 14, for IL-6 receptor in 14 and for G-CSF in five patients. Only in one patient a complex rearrangement of the G-CSF gene with possible amplification was noted indicating rarity of direct alterations of growth factor genes in acute myelogenous leukemia (AML). Spontaneous m-RNA expression for GM-CSF was found in only one of 20 patients, and for IL-6 in eight of 11 patients. In vitro incubation of AML cells of eight patients with recombinant tumor necrosis factor for 24 hr revealed induction of GM-CSF m-RNA expression in three cases and GM-CSF protein expression in two of them. These data suggest that spontaneous GM-CSF production occurs rarely in AML and that monokines, such as tumor necrosis factor, may induce GM-CSF in AML cells. Therefore, interactions of AML cells with normal or malignant accessory cells may be important for autocrine stimulation in AML. Our data suggest that ectopic growth factor secretion is not the primary cause of generating AML but may contribute to progression of the disease. Alternatively, AML may represent a heterogenous group of leukemias with different etiology but similar phenotype.

Blotting, Northern↗

PubMed1985

Isolation and characterization of My23, a myeloid cell-derived antigen reactive with the monoclonal antibody AML-2-23.

In this study, we describe the isolation and characterization of My23, a human myeloid antigen defined by the monoclonal antibody (MoAb) AML-2-23. Cells of the HL-60 human promyelocytic cell line, when cultured in the presence of 1,25-dihydroxyvitamin D3 (calcitriol), express a surface protein of approximately 50 to 55 kilodaltons (Kd) which was immunoprecipitated with the AML-2-23 MoAb. Furthermore, after 2 days of exposure to calcitriol, HL-60 cells began to release My23 into culture medium, as determined by the ability of culture supernatant from these cells to block the binding of AML-2-23 to myeloid cells. My23 release was almost totally inhibited by incubation of cells at 4 degrees C, and was partially blocked by treatment of cells with cycloheximide or tunicamycin. The culture supernatant blocking factor, soluble My23, was identified as a 45 to 50 Kd protein by Western blot/immune overlay, using AML-2-23 and an 125I-labeled second antibody. My23, which was affinity-purified from culture supernatant, retained the ability to block AML-2-23 binding to myeloid cells. The affinity-purified antigen migrated on SDS-PAGE as a diffuse band in the m.w. range of 44 to 52 Kd. On treatment with endoglycosidase, the apparent m.w. of My23 decreased to approximately 40,000, indicating the presence of carbohydrate residues on My23. Serum from mice immunized with the purified antigen reacted with the same spectrum of myeloid cells as AML-2-23 MoAb, reacted with the My23 soluble protein in immunoblots, and competed with AML-2-23 for binding to myeloid cells. Binding of this antiserum to myeloid cells was blocked by cell supernatant from both monocytes and calcitriol-treated HL-60 cells, suggesting, along with results from m.w. determinations of the two preparations, that the soluble and cell surface forms of My23 are similar. Moreover, based on our finding that human plasma specifically inhibits the binding of AML-2-23 to myeloid cells, My23 may also be released in vivo. The enhanced expression of My23 on activated and more mature myeloid cells and its shedding or secretion by these cells is consistent with a functional role for My23.

Antibodies, Monoclonal↗

PubMed1994

AML: immunophenotypic heterogeneity and prognostic significance of c-kit expression.

Antigenic profiles in AML that have generally accepted prognostic significance, and allow treatment stratification, have not yet been defined. In a previous report of Ashman et al., the proto-oncogene c-kit defined by binding of the moab YB5.B8 was expressed on about one third of AML cases, mainly of the undifferentiated FAB-subtypes and associated with poor prognosis and overall survival. In this study, the moab 17F11 also directed against the c-kit structure stained 41/47 AML and 6/8 CML blast specimens, whereas all investigated 40 ALL samples were c-kit negative. c-kit was not restricted to any particular, undifferentiated FAB-subtype, but found in 9/9 AML-M0/M1, 18/19 AML-M2, 0/1 AML-M3, 11/13 AML-M4 and 3/5 AML-M5 subtypes. Immunophenotypical analysis showed no restriction of c-kit expression to immature, CD34+ precursors, but c-kit was also expressed on CD4+ CD34- precursor cells differentiating towards the monocyte lineage. In addition, multi-color labelings revealed an extraordinary heterogeneity of concomitant antigen expression on c-kit+ cells 10/36 c-kit+ CD34+ samples expressing CD56 and 16/36 c-kit+ CD34+ samples being CD7 positive; two c-kit+ CD34+ specimens carried the B-cell antigen CD19. In correlation to clinical outcome c-kit expression as single parameter was not predictive for poor response to therapy and short survival as previously suggested.

Aged↗

PubMed1993

Detection of residual disease in AML patients by use of double immunological marker analysis for terminal deoxynucleotidyl transferase and myeloid markers.

In the majority of patients with acute myeloid leukemia (AML) immature leukemic subpopulations expressing myeloid markers and terminal deoxynucleotidyl transferase (TdT) are present. The normal counterparts of these double-positive cells are rare in bone marrow (BM) (< 0.03%; if they occur at all) and are not detectable in peripheral blood (PB). In 14 patients with TdT+ AML at diagnosis, we have performed a prospective follow-up study to monitor the myeloid-marker+, TdT+ cells during and after chemotherapy. One patient did not obtain complete remission (CR), a second patient relapsed under therapy, whereas the other 12 patients were in cytomorphological CR at the end of chemotherapy. During subsequent follow-up, seven of these 12 patients developed one or two relapses (total of ten relapses). Nine of these ten relapses were preceded by a gradual increase of myeloid-marker+, TdT+ cells in BM and PB samples over a period of 14-38 weeks. Based on comparable results in BM and PB samples and doubling times of 15-20 days, we propose that monitoring of AML patients should include PB sampling each 4-6 weeks. In one patient the relapse was not preceded by a gradual increase of double-positive cells. This false negative result was caused by a phenotypic shift, since at relapse the AML cells did not express TdT. In the five AML patients who still are in continuous cytomorphological CR for 32-46 months we repeatedly detected relatively high percentages of myeloid-marker+, TdT+ cells in BM (up to 0.1%) and PB (up to 0.02%). Although we could not prove the leukemic origin of these double-positive cells, they might represent residual dysplastic AML cells which survived chemotherapy but which are not capable of causing leukemia regrowth as yet. This would be in line with recent polymerase chain reaction studies, which could demonstrate the persistence of leukemic clones in the majority of AML patients in continuous CR. It is concluded that double immunofluorescence labeling for myeloid markers and TdT is useful for detection of residual disease in TdT+ AML patients. A gradual increase of double-positive cells is suggestive for leukemic cell growth and can be used to predict relapse.

Acute Disease↗

PubMed2000

SCF, IL-1beta, IL-1ra and GM-CSF in the bone marrow and serum of normal individuals and of AML and CML patients.

This study compared cytokine transcript and protein levels in BM cells of normal individuals and leukemic patients. AML differed from normal in that: (1) AML marrow cells contain more IL-1beta protein than normal cells, (2) IL-1ra transcripts are absent from AML marrow cells, (3) AML marrow serum contains less IL-1ra protein than normal, (4) peripheral blood and marrow serum of AML patireents contains more SCF protein than normal serum, and (5) SCF transcripts have been detected in AML marrow biopsies and not in aspirate cells. These data suggest that unbalanced cytokine production may make a significant contribution to the abnormal behaviour of AML cells.

Biopsy↗