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PubMed2003

Prognostic significance of FLT3 ITD and D835 mutations in AML patients.

Both ITD and D835 mutations of the fms-like tyrosine kinase (FLT3) gene cause constitutive activation of the receptor, in the absence of ligand. We have examined a cohort of 91 patients, AML (80) and MDS (11), to determine the prevalence of these mutations and any correlations between the two mutations and disease prognosis. FLT3/ITD (ITD+) or D835 mutations (D835+) were not detected in MDS patients examined. However, 10% (8/80) and 7.5% (6/80) of AML patients were ITD+ and D835+, respectively. ITD+ patients have a higher rate of relapse than patients with wild-type (WT) FLT3. Median overall survival was 4.6 months (range 0.6-36.2) for ITD+ and 19.85 months (range 0.2-197.5) for WT patients (P=0.0066), and disease-free survival (DFS) was also worse for ITD+ patients than FLT3/WT patients (P=0.047). FLT3/ITD is also a significant prognostic marker for overall survival (OS) and DFS in patients in the standard karyotype group (P=0.0040, 0.0365, respectively). ITD is more prevalent in patients in the standard karyotype category (7/41, 17.1%) as compared to patients in the poor-risk category (1/32, 3.1%). Similar to ITD, D835 mutations were found to be more frequent in patients with standard-risk rather than poor-risk cytogenetic category. WBC count (mean 63.8 x 10(9)/l) was significantly higher in ITD+ patients than patients with D835 mutations (mean 34.8 x 10(9)/l) and WT patients (mean 26.4 x 10(9)/l) (P=0.004). D835 mutants did not appear to have a worse median OS or DFS compared with the WT group. We conclude that FLT3/ITD mutations may be an important prognostic marker in AML, especially in the standard/good risk karyotype groups, where it may allow risk-directed therapy.

Acute Disease↗

PubMed2003

Comparison between conventional banding analysis and FISH screening with an AML-specific set of probes in 260 patients.

Fluorescence in situ hybridization (FISH) is becoming popular in the diagnosis of clonal chromosomal abnormalities. We set up a fast FISH procedure using an extensive set of specific probes. Conventional banding analysis (CBA) and FISH were compared in 260 newly diagnosed acute myeloid leukemia (AML) patients. For FISH the following probes were used: MLL, CBF-beta/MYH11, ETV-6/AML1; AML1/ETO, BCR/ABL, PML/RAR, c-MYC, TP53, RB1, 5q31/5p15.2, 5q33-34, 7q31/CEP7, 20q13; CEP 4, X, Y. Result time was 96 h for CBA versus 5 h for FISH from direct harvest. CBA showed clonal abnormalities in 41% (n=105/260), normal karyotype in 39% (n=102/260) and failed in 20% (n=53/260). FISH screened all patients and detected abnormalities in 39% (n=102/260); CBA and FISH together identified abnormalities in 49% (n=128/260). In six patients with normal CBA and in eight patients with clonal karyotype, it detected further cryptic abnormalities. CBA showed clonal abnormalities in 13% of patients negative at FISH (n=21/158). FISH screening does not add relevant information to CBA, but is the quickest method for detecting major genetic abnormalities in AML. The speed of FISH is very valuable in AML-M3/M3v because PML/RAR+ patients require specific therapy. Furthermore, we suggest FISH screening in failed, complex or suboptimal quality chromosome and specific FISH analysis for 5q, 7q, 12p, 17p, inv(16), t(11q23) in order to implement CBA accuracy.

Acute Disease↗

PubMed1996

Susceptibility of AML cells to in vitro apoptosis correlates with heat shock protein 70 (hsp 70) expression.

Acute myeloid leukaemia (AML) cells from some individuals rapidly undergo apoptosis during in vitro culture. We have analysed this mode of cell death in AML cells harvested from patients at initial presentation and during subsequent treatment/relapse. Using flow cytometric analysis of propidium iodide-stained cells and quantitation of the subdiploid apoptotic peak, we observed that leukaemic cells from patients with AML displayed a heterogenous susceptibility to apoptosis in terms of the rate of accumulation of apoptotic cells. After 48 h incubation in the absence of added serum or exogenous growth factors the percentage of apoptotic cells ranged from 3% to 99%. This susceptibility to apoptosis correlated significantly with intracellular expression of hsp70 (P = 0.009), but not hsp90, and was also associated with the presence of p53 and low levels of expression of bcl-2.

Acute Disease↗

PubMed1997

The significance of trisomy 8 in de novo acute myeloid leukaemia: the accompanying chromosome aberrations determine the prognosis. German AML Cooperative Study Group.

Trisomy 8 is the most frequent numerical chromosome aberration in acute myeloid leukaemia (AML). It occurs either as the sole anomaly or together with other clonal chromosome aberrations. We investigated whether accompanying chromosome anomalies influence the clinical outcome in patients with trisomy 8 and de novo AML. Since 1986, in 713 AML cases treated according to the protocols of the German AMLCG trials, chromosome analyses have been successfully performed. The overall incidence of trisomy 8 was 7.6%. Complete clinical follow-up data were available for 51 patients who were divided into three different categories: group 1: trisomy 8 as the sole cytogenetic anomaly (n = 20); group 2: trisomy 8 in addition to favourable chromosome aberrations (t(8;21)(q22;q22), t(15;17)(q22;q21), inv(16)(p13q22)) (n = 10); and group 3: trisomy 8 accompanied by other anomalies, in most cases of complex type (n = 21). Complete remission (CR) rates were 70%, 90% and 67% for groups 1, 2 and 3, respectively. Event-free survival (EFS) at 3 years differed significantly between patients with trisomy 8 only (37.5%), patients with trisomy 8 in combination with favourable aberrations (55.0%) and patients with trisomy 8 and other accompanying anomalies, mostly complex chromosome aberrations (9.0%) (group 1 v group 2: P=0.12; group 1 v group 3: P=0.005; group 2 v group 3: P=0.05). In this study patients with +8 as the sole cytogenetic anomaly had an intermediate prognosis, patients with +8 in addition to favourable chromosome aberrations maintained a good clinical outcome, and patients with +8 in combination with other abnormalities showed the worst prognosis.

Acute Disease↗

PubMed1997

Incidence of AML1/ETO fusion transcripts in patients entered into the MRC AML trials. MRC Adult Leukaemia Working Party.

Acute myeloid leukaemia (AML) with the t(8;21)(q22;q22) is deemed to be a 'good-risk' disease. 396 patients with AML at diagnosis were screened for the presence of t(8;21) and AML1/ETO fusion transcripts by cytogenetic and RT-PCR techniques respectively. 32 cases of t(8;21) were detected, all of which were also PCR positive. A further 19 cases were detected at the molecular level, predominantly but not exclusively in M1 and M2 FAB types. Approximately 12% of all new cases of AML are estimated to have AML1/ETO fusion transcripts and it is suggested that molecular screening should be performed in all cases with the possible exception of the M3 FAB type.

Acute Disease↗

PubMed1998

Novel enzymatic abnormalities in AML and CML in blast crisis: elevated leucocyte leukotriene C4 synthase activity paralleled by deficient leukotriene biosynthesis from endogenous substrate.

Leukotrienes (LT) are inflammatory mediators which can also exert regulatory effects on human myelopoiesis. We have studied the LT-producing capacity of freshly isolated leucocyte suspensions (containing blast cells in variable proportions) from 41 patients with acute myeloid leukaemia (AML) or chronic myeloid leukaemia (CML) in blast crisis (CMLbc) at diagnosis or relapse/resistant disease. Leucocyte suspensions from 19/29 AML patients (66%), and 2/12 CMLbc patients (17%; P = 0.012) demonstrated deficient capacity to synthesize LT from endogenous substrate after ionophore A23187 stimulation. Thus, these cells produced < 8 pmol LTB4+LTC4/10(6) cells (< 20% of mean LT formation in leucocyte suspensions from 18 healthy subjects). Addition of exogenous arachidonic acid did not normalize the LT synthesis in poor-producing cell suspensions. Purified, morphologically mature granulocytes from two AML patients also failed to produce normal amounts of LT. In leucocyte suspensions from the remaining 20 AML/CMLbc patients A23187 provoked LT biosynthesis, with markedly increased production of LTC4, but decreased LTB4 formation. Furthermore, elevated conversion of exogenous LTA4 to LTC4 was noted in the patient samples, independent of their capacity to produce LT after A23187 stimulation. The percentage of blast cells in patient white blood cell differential counts correlated inversely with ionophore-induced LT synthesis, but positively with the conversion of exogenous LTA4 to LTC4. The results suggest elevated LTC4 synthase activity and suppressed 5-lipoxygenase activity as novel enzymatic features of myeloid leukaemia patients with immature phenotype.

Acute Disease↗

PubMed1999

A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. United Kingdom Medical Research Council's Adult and Childhood Leukaemia Working Parties.

Data on 1711 patients, aged up to 55 years, in the MRC AML 10 trial were used to create a prognostic index for use in risk-directed therapy decision making for younger patients with acute myeloid leukaemia (AML). Two parameters, response after course 1 and cytogenetics, were strongly predictive of outcome. For patients with complete remission, partial remission and resistant disease, 5-year survival from the start of course 2 was 53%, 44% and 22% and relapse rates were 46%, 48% and 69% respectively, and for patients with favourable, intermediate and adverse karyotypic abnormalities, survival was 72%, 43% and 17% and relapse rates were 34%, 51% and 75% respectively (all P < 0.0001). Patients with FAB type M3 but no cytogenetic t(15;17) also had a low relapse rate (29%). These three factors were combined to give three risk groups: good (favourable karyotype or M3, irrespective of response status or presence of additional abnormalities), standard (neither good nor poor), poor (adverse karyotype or resistant disease, and no good-risk features). Survival for these three groups was 70%, 48% and 15% respectively and relapse rates were 33%. 50% and 78% (both P < 0.0001). The index is simple (based on just three parameters), robust (derived from 1711 patients), highly discriminatory (55% survival difference between good and poor risk) and validated, so can be applied in the clinical setting to assist with therapeutic decisions as in the current AML 12 trial.

Acute Disease↗

PubMed1999

Double esterase staining of the bone marrow contributes to lineage identification in a case of minimally differentiated acute myeloid leukaemia (AML M0).

Minimally differentiated acute myeloid leukaemia (AML-M0) may pose difficulty in diagnosis since morphological criteria alone are not reliable. Other studies such as electron microscopy, immunocytochemistry and surface marker analysis are needed. The role of cytochemistry has been limited to the negative staining of blasts for Sudan Black B and myeloperoxidase. An abnormal morphology and cytochemistry of bone marrow maturing cells may indicate the myeloid nature of acute leukaemia. In this case of AML-M0, increased numbers of maturing and mature bone marrow granulocytic cells staining simultaneously for both specific and non-specific esterase (double esterase) are described. In acute leukaemia, this abnormal cytochemical finding seems to be specific for myeloid leukaemia and may be used as supplementary evidence of myeloid differentiation of morphologically undifferentiated blasts in cases of AML-M0.

Acute Disease↗

PubMed2002

Immunological evaluation of minimal residual disease (MRD) in acute myeloid leukaemia (AML).

Immunophenotypic analysis of leukaemic cells using multiparametric flow cytometry has proved to be an attractive approach for MRD investigation in acute lymphoblastic leukaemia (ALL); by contrast, information on acute myeloid leukaemia (AML) is still scanty. Here, we first review the methodological strategies for these studies. Triple or quadruple antigenic combinations, analysed by multiparametric flow cytometry, have shown that in 80% of AML patients it is possible to identify aberrant or uncommon phenotypic profiles on blast cells, thereby allowing their distinction from normal cells and their use as leukaemia-associated phenotypes (LAP). We also focus on technical aspects that are important in the definition of LAP. We then review pitfalls that could potentially affect results using this approach. Finally, we review available information concerning the clinical value of these studies. Although reported data in the literature are still scanty, several authors have shown that this technique could be used for the prognostic evaluation of AML patients, when immunophenotypic evaluation is applied after induction therapy.

Acute Disease↗

PubMed2000

Smad and AML proteins synergistically confer transforming growth factor beta1 responsiveness to human germ-line IgA genes.

Transcription of germ-line immunoglobulin heavy chain genes conditions them to participate in isotype switch recombination. Transforming growth factor-beta1 (TGF-beta1) stimulates promoter elements located upstream of the IgA1 and IgA2 switch regions, designated Ialpha1 and Ialpha2, and contributes to the development of IgA responses. We demonstrate that intracellular Smad proteins mediate activation of the Ialpha1 promoter by TGF-beta. TGF-beta type 1 receptor (ALK-5), activin type IB receptor (ALK-4), and the "orphan" ALK-7 trans-activate the Ialpha1 promoter, thus raising the possibility that other members of the TGF-beta superfamily can also modulate IgA synthesis. Smads physically interact with the AML family of transcription factors and cooperate with them to activate the Ialpha1 promoter. The Ialpha1 element provides a canapé of interspersed high and low affinity sites for Smad and AML factors, some of which are indispensable for TGF-beta responsiveness. While AML.Smad complexes are formed in the cytoplasm of DG75 and K562 cells constitutively, only after TGF-beta receptor activation, novel Smad3.Smad4.AML complexes are detected in nuclear extracts by EMSA with Ialpha1 promoter-derived probes. Considering the wide range of biological phenomena that AMLs and Smads regulate, the physical/functional interplay between them has implications that extend beyond the regulation of class switching to IgA.

Base Sequence↗

PubMed2000

Transcriptional regulation of the transforming growth factor-beta -inducible mouse germ line Ig alpha constant region gene by functional cooperation of Smad, CREB, and AML family members.

Smads regulate transcription of defined genes in response to transforming growth factor-beta (TGF-beta) receptor activation. This process involves functional cross-talk of Smads with transcription factors at responsive DNA elements to achieve maximal transcription activation and specificity. TGF-beta has been shown to induce transcription of the germ line (GL) Ig alpha constant region gene and to direct class switching to IgA antibodies. It has been shown that acute myeloid leukemia (AML) transcription factors cooperate with Smad3 to stimulate transcription from the GL Ig alpha constant region gene promoter. We report here that the TGF-beta-induced transcription from this promoter requires DNA binding of cAMP-response element-binding protein (CREB) to the nearby ATF/cAMP-response element site and of Smads to a nearby Smad binding sequence. At these sites, Smad3/4 cooperates with CREB to activate transcription in response to TGF-beta, and disruption of either binding sequence abolished TGF-beta-induced transcription. In addition, AML1 or AML2 also binds to the promoter and cooperates with Smad3/4, and in this way further enhances the TGF-beta-induced transcriptional activation of the GL Ig alpha promoter. Thus, whereas Smad3/4, CREB, and AML family members bind independently to the respective DNA sequences in the GL Ig alpha promoter, functional synergy of Smads with CREB and AML proteins results in maximal TGF-beta-induced transcription.

Animals↗

PubMed2006

Over-expression of angiotensin-converting enzyme (CD 143) on leukemic blasts as a clue for the activated local bone marrow RAS in AML.

Local bone marrow renin-angiotensin system (RAS) is an autocrine-paracrine system affecting hematopoiesis. Angiotensin II type 1a (AT1a) receptors are present on the CD34+ hematopoietic stem cells. Angiotensin II stimulates the proliferation of bone marrow and umbilical cord blood hematopoietic progenitors. There are preliminary data that local RAS might also be involved in leukemogenesis. ACE hyper-function may lead to the acceleration of negative hematopoietic regulator peptide, AcSDKP, metabolism, which in turn lowers its level in the bone marrow micro-environment, finally removing the anti-proliferative effect of AcSDKP on the hematopoietic cells and blasts. Renin expression could have a role on the leukemia development and angiotensin may act as an autocrine growth factor for acute myeloid leukemia (AML) cells. The aim of this study is to search ACE (CD 143) surface antigen by flow-cytometric analyses on the leukemic blast cells taken from the bone marrow of the patients with AML. Bone marrow aspiration materials and peripheral blood samples were obtained from 11 patients with AML (eight males, three females; aged 46 (range 26-67) years) and six patients with non-malignant hematological disorders (four males, two females; aged 56 (range 22-71) years). ACE (CD 143) surface antigen was shown to be over-expressed in leukemic myeloid blast cells. ACE is positively correlated with bone marrow blast count. Elucidation of the pathological activity of the local RAS-mediated regulation of the leukemogenesis is both pathobiologically and clinically important, since the angiotensin peptides represent a molecular target in the disease management.

Acute Disease↗

PubMed2003

Intensified myeloablative therapy and autologous stem-cell transplantation for patients with AML: single center experience.

BACKGROUND: Thirty-seven consecutive individuals in CR of AML received intensified conditioning and autologous stem-cell transplantation. METHODS: For those receiving PBSC (n = 28), mobilization protocol was with cyclophosphamide 60 mg/kg followed by G-CSF injection at 5-10 microg/kg; stem cells were harvested by large volume apheresis (6-8 blood volumes) and then cryopreserved. Ablative therapy consisted of fractionated TBI (total 12 Gy), followed by four fractions (1.5 Gy each) of total nodal irradiation (TNI), and CY 120 mg/kg under mesna cover. RESULTS: For individuals transplanted in CR 1 (n = 31) the median time from diagnosis to grafting was 167 (range 92 - 212) days. Patients transplanted with PBSC received high number of CFU-GM x 10(4)/kg (P < 0.01), a difference that was associated with a significantly shorter platelet recovery. While there was no early transplant-associated mortality, in 10 patients death was caused by recurrence of the disease. The median survival is 1746 (range 105-4467) days and 26 (70%) survive disease free, at a median 2207 (range 698-4467) days from transplantation. Multivariate analysis showed that survival of patients with AML-M3, receiving higher CFU-GM (P = 0.04) and without morphological dysplasia (P = 0.01) was longest. DISCUSSION: For patients in remission of AML, transplantation with PBPC appears to be an effective form of intensification, particularly when TBI + TNI (delivering a total of 18 Gy to the axial skeleton) were used as conditioning.

Adolescent↗

PubMed2006

AML-loaded DC generate Th1-type cellular immune responses in vitro.

BACKGROUND: The generation of AML-specific T-lymphocyte responses by leukemia-derived DC has been documented by multiple investigators and is being pursued clinically. An obstacle to widespread use of this strategy is that it has not been possible to generate leukemic DC from all patients, and an alternative approach is needed if the majority of leukemia patients are to receive therapeutic vaccination in conjunction with other treatment protocols. METHODS: In the present study, we generated DC from CD14-selected monocytes isolated from healthy donor PBPC and loaded them with a total cell lysate from AML patient blasts. RESULTS: Immature in vitro-derived DC exhibited robust phagocytic activity, and mature DC demonstrated high expression of CD80, CD83, CD86 and the chemokine receptor CCR7, important for DC migration to local lymph nodes. Mature, Ag-loaded DC were used as APC for leukemia-specific cytotoxic T-lymphocyte (CTL) induction and demonstrated cytotoxic activity against leukemic targets. CTL lysis was Ag-specific, with killing of both allogeneic leukemic blasts and autologous DC loaded with allogeneic AML lysate. HLA-matched controls were not lysed in our system. DISCUSSION: These data support further research into the use of this strategy as an alternative approach to leukemia-derived DC vaccination.

Acute Disease↗

PubMed1987

Differential pattern of oncogene and beta-actin expression in leukaemic cells from AML patients.

The presence of mRNA hybridizing to five oncogene (fos, mos, myc, sis, abl) and a beta-actin probe(s) was studied with a semiquantitative dot-blot procedure in eight AML patients. Around 10(7) leucocytes, corresponding to 1-10 ml blood, sufficed for the analysis. Each patient, regardless of the FAB group, exhibited a distinct pattern of oncogene or beta-actin expression. Especially strong signals were obtained with the beta-actin probe in two patients and with the fos probe in three patients. The findings underscore the heterogeneity of AML, either present from the first step towards malignancy or arising during the progression of the disease. The pattern of oncogene expression in leukaemic cells studied in routine blood samples may become an additional means for classification and follow-up of AML patients.

Actins↗

PubMed1994

Blast cells in child and adult AML: comparative study of morphocytochemical, immunological and cytogenetic characteristics.

Bone marrow blast cells of 174 child and 188 adult patients with AML were examined and characterized in terms of their FAB type, immunological phenotype (102 children, 123 adults) and karyotype (69 children, 95 adults). The incidence of FAB variants of AML proved similar in children and adults. In patients under 15 and over 60, peroxidase activity in myeloblasts was lower than in middle-aged patients. Similar rates of HLA-Dr. Thy-1, CD11a, T-cell antigens, CD19, Gly-A and Eb antigens were found in cells of child and adult patients. The frequency of CD11b, CD38 and CD10 antigen expression on blast cells was higher in children than in adults. Abnormal blast karyotype was noted in 81.8% of children and 73.7% of adults. Translocation (8;21) was usually found in cases of M2 type (82%), significantly more frequently in children. predominantly in the group aged 6-10. t(15;17) was detected in all age groups only in M3 type of cells (86%). t(9;22) occurred more frequently in adults than in children; t(11q23) incidence rates were somewhat higher in children than in adults. Three cases of AML in children are described with deletion of chromosome 5 in their leukaemic cells. The data obtained indicate different biological characteristics of blast cells in children and adults. It is likely that haemopoietic cell involvement in children under 2 years and adult patients over 60 occurs at earlier stages than in middle-aged patients.

Acute Disease↗

PubMed2004

The expression of P-glycoprotein in AML cells with FLT3 internal tandem duplications is associated with reduced apoptosis in response to FLT3 inhibitors.

P-glycoprotein (pgp), a membrane efflux pump, is recognized to have an anti-apoptotic function. Internal tandem duplications (ITDs) of the Fms-like tyrosine kinase 3 (FLT3) receptor are the most common mutations in acute myeloid leukaemia (AML). Both ITDs and pgp positivity confer an adverse clinical prognosis. FLT3 inhibitors induce variable apoptosis in cell lines transfected with FLT3 ITDs. We studied the effect of herbimycin A, AG1296 and PKC412 on primary AML blasts. All compounds showed significantly higher cell kill after 48-h incubation in samples with an ITD compared with wild type (Herbimicin P < 0.001; AG1296 P = 0.001, PKC412, P = 0.002). Pgp-positive samples were significantly less sensitive to herbimycin and AG1296 than pgp-negative samples, although neither molecule inhibited the efflux function of pgp. The concurrent incubation with the pgp inhibitor PSC833 resulted in an enhanced cell kill in 4/5 ITD pgp-positive samples versus two of nine ITD pgp-negative samples. PKC412 inhibited pgp function and induced cell death in FLT3 ITD/pgp-positive samples. We conclude that AML samples with a FLT3 ITD are more susceptible to these inhibitors than wild-type samples. However, the expression of pgp in cells with FLT3 ITDs can reduce their sensitivity to FLT3 inhibitors and therefore pgp expression should be assessed in clinical trials of FLT3 inhibitors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Del (9q) AML: clinical and cytological characteristics and prognostic implications.

Del (9q) is a recurrent cytogenetic abnormality in acute myeloid leukaemia (AML). We report an analysis of 81 patients with del(9q) as a diagnostic karyotypic abnormality entered into the Medical Research Council AML trials 10, 11 and 12. Patients were divided into three groups: (i) Sole del (9q), 21 patients; (ii) Del(9q) in association with t(8;21), 29 patients; (iii) Del(9q) in association with other cytogenetic abnormalities, 31 patients. Sole del(9q) was associated with a characteristic bone marrow phenotype at diagnosis: a single Auer rod was found in all cases examined. There was also an association with erythroid dysplasia (74%) and granylocytic lineage vacuolation (90%). The incidence of all three of these features was significantly higher (P < 0.05) in the sole del(9q) group compared with control cases lacking del(9q). The overall survival (OS) of all 81 patients was compared with a control group of 1738 patients with normal cytogenetics entered in the same trials over the period of investigation. The 5-year OS for patients with del(9q) was 45%, compared with 35% for the control group (P = 0.09). Patients with del(9q) in association with t(8;21) had a 5-year OS of 75%, which was significantly better than the groups with either sole del(9q) (40%) and del(9q) with other abnormalities (26%; P = 0.008). Karyotyping indicated a common area of deletion in the region 9q21-22, which was present in 94% of cases. It is likely that the deletion of single or multiple tumour suppressor genes located in this region may underlie the pathogenesis of del (9q) AML.

Acute Disease↗