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PubMed2003

Novel translocation in acute megakaryoblastic leukemia (AML-M7).

The authors report a unique translocation in a patient with M7 acute myeloid leukemia and review the literature. A 22-month-old girl without Down syndrome was diagnosed with acute myeloid leukemia, subtype M7 (AML-M7), and died with relapsed disease following bone marrow transplantation. Tumor cells were evaluated using cytogenetics (including spectral karyotyping), immunohistochemistry, and flow cytometry. The patient was found to have a previously unreported complex translocation as follows: 50,XX,der(1)t(1;5)(p36?.1;p15?.1),del(5)(p15?.1), +6,+der(6;7)(?;?),der(7)t(6;7)(?;p22)[2],der(9)t(6;9) (?;p21)t(9;14)(q34;q11.2-q13),+10,t(12;16)(p13;q24),-14[2], del(14)(q13)[2],+der(19)t(1;19)(?;p13.3),+22[cp 4]. AML-M7 in non-Down syndrome patients is a rare disease that requires improved prognostic markers.

Bone Marrow Transplantation↗
PubMed2004

Childhood acute myelomonocytic leukemia (AML-M4) presenting as catastrophic antiphospholipid antibody syndrome.

: The authors describe a 15-year-old girl presenting with a cerebral ischemic stroke as the first manifestation of catastrophic antiphospholipid antibody syndrome secondary to acute myeloid leukemia (AML). Despite treatment with anticoagulants, therapeutic plasma exchange, and chemotherapy, the patient developed multiorgan thromboses and failure, eventually culminating in death. This unusual presentation of AML has not been previously described in children. Clinical features of antiphospholipid antibody syndrome and current knowledge regarding its association with malignancies are reviewed.

Adolescent↗
PubMed2005

High activity and incomplete cross resistance of nucleoside analogues cladribine and fludarabine versus Ara-C on leukemic cells from patients with AML.

The in vitro activity and cross-resistance pattern of the purine analogues cladribine and fludarabine and the pyrimidine analogue cytarabine on leukemic cells from 170 patients with AML was evaluated using a bioluminescence assay. In in vivo mimicking concentrations, cladribine (50 nmol/L) and fludarabine (2 micromol/L) were more cytotoxic than cytarabine (0.5 micromol/L). The cytotoxic effect of fludarabine correlated weakly to cytarabine (r = 0.37, P < 0.001). The cytotoxic effect of cladribine correlated better to cytarabine (r = 0.49, P = 0.0002) but best to fludarabine (r = 0.82, P < 0.001). There was an absence of correlation between either cladribine or fludarabine and daunorubicin (0.2 micromol/L). Of 45 highly Ara-C-resistant samples, cladribine exerted high or intermediate effect in 54% and fludarabine in 52%. These in vitro data indicate that cladribine and fludarabine are active drugs in the treatment of AML. The cross resistance to cytarabine was not complete, and the drugs can be valuable either as alternatives to Ara-C or in combination therapy for treatment of leukemia resistant to standard therapy.

Adult↗
PubMed1997

ALY, a context-dependent coactivator of LEF-1 and AML-1, is required for TCRalpha enhancer function.

LEF-1 is a transcription factor that participates in the regulation of the T-cell receptor alpha (TCR alpha) enhancer by facilitating the assembly of multiple proteins into a higher order nucleoprotein complex. The function of LEF-1 is dependent, in part, on the HMG domain that induces a sharp bend in the DNA helix, and on an activation domain that stimulates transcription only in a specific context of other enhancer-binding proteins. With the aim of gaining insight into the function of context-dependent activation domains, we cloned ALY, a novel LEF-1-interacting protein. ALY is a ubiquitously expressed, nuclear protein that specifically associates with the activation domains of LEF-1 and AML-1 (CBF alpha2, PEBP2 alpha(B), which is another protein component of the TCR alpha enhancer complex. In addition, ALY can increase DNA binding by both LEF-1 and AML proteins. Overexpression of ALY stimulates the activity of the TCR alpha enhancer complex reconstituted in transfected nonlymphoid HeLa cells, whereas down-regulation of ALY by anti-sense oligonucleotides virtually eliminates TCR alpha enhancer activity in T cells. Similar to LEF-1, ALY can stimulate transcription in the context of the TCR alpha enhancer but apparently not when tethered to DNA through an heterologous DNA-binding domain. We propose that ALY mediates context-dependent transcriptional activation by facilitating the functional collaboration of multiple proteins in the TCR alpha enhancer complex.

Amino Acid Sequence↗
PubMed1981

Distribution of 250 cases of acute myeloid leukaemia (AML) according to the FAB classification and response to therapy.

250 consecutive cases of AML in adults were diagnosed over a 6 year period in the same institution. Pretreatment blood and bone marrow smears and also cytochemical markers were taken into account in the study. All cases were reviewed by three different observers and classified according to the FAB criteria. The final diagnosis resulted from agreement of at least two observers. Some discrepancies occurred in the classification and are discussed. The prognostic implication of AML subclassification was assessed as the percentage of complete remission in 100 cases.

Adolescent↗
PubMed1988

Interleukin 3 enhances the cytotoxic activity of 1-beta-D-arabinofuranosylcytosine (ara-C) on acute myeloblastic leukaemia (AML) cells.

We have evaluated the possibility of enhancing the cell killing effect of ara-C on AML blasts by increasing their proliferative activity with haemopoietic growth factors. Leukaemic cells from 10 AML patients were incubated for 3 d in liquid culture in the presence or in the absence of the human recombinant growth factors IL-1 beta (5 U/ml) and IL-3 (3 U/ml), and subsequently exposed to ara-C (3 micrograms/ml) for the last 24 h. The number of residual leukaemic stem cells was evaluated by a clonogenic assay in semisolid medium. The results showed that ara-C exposure inhibits the proliferation of a higher proportion of clonogenic cells in cultures pretreated with growth factors than in the controls (mean inhibitory values: in the absence of growth factors = 49.8%; with IL-1 beta = 58.3%; with IL-3 78.9%). The effect was statistically significant only when IL-3 was used as a growth factor. The results suggest that haemopoietic growth factors may help to improve the therapeutic index of cytostatic agents.

Cell Survival↗
PubMed1988

Transferrin receptor expression of AML blasts is related to their proliferative potential.

Expression of the transferrin receptor (TfR) was studied on peripheral blood blast cells from 11 patients with acute myeloid leukaemia (AML). Using a monoclonal anti-TfR antibody (OKT9) and a polyclonal antibody against surface membrane-bound transferrin, a proportion of blasts from all the patients was found to express receptors for transferrin. Further analysis of OKT9 expression using a fluorescent activated cell sorter (FACS) showed that the TfR was heterogeneously distributed in the blast cell population. In five out of six samples studied, stimulation of DNA synthesis following short-term culture induced a several-fold increase in TfR display as analysed by flow cytometry using OKT9 or FITC-conjugated transferrin. Blasts from seven patients stained with OKT9 were separated on the FACS into positive and negative or weakly positive fractions. Culture of the TfR negative population in a blast cell colony assay produced no colonies in either of two patients. In a further five patients the colony forming cells were predominantly associated with the TfR strongly positive fraction (52 +/- 25 colonies/10(4) cells) rather than the TfR weakly positive fraction (12 +/- 11 colonies/10(4) cells). Analysis of colony size showed that clones derived from the weakly positive fraction were smaller than clones from the TfR strongly positive fraction. These results suggest that TfR display by AML blasts is related to their proliferative capacity and is expressed by the leukaemic stem cell fraction.

Antibodies, Monoclonal↗
PubMed1989

The recovery of circulating progenitor cells after chemotherapy in AML and ALL and its relation to the rate of bone marrow regeneration after aplasia.

Peripheral blood levels of BFU-e, CFU-GM and CFU-mix were studied serially in nine patients with acute leukaemia in remission during the period of recovery that followed induction or consolidation chemotherapy. Following 23 courses of treatment in the nine patients, the values for all three classes of progenitor were found to be higher in ALL than in AML (mean peak CFU-GM levels 5.8 x 10(3)/ml and 0.8 x 10(3)/ml respectively) and the highest levels were observed in patients recovering the most rapidly from bone marrow aplasia. Peak levels of these progenitors correlated best with the rate and extent of platelet recovery and all patients achieving blood levels of greater than 1.0 x 10(3) CFU-GM/ml had recovered greater than 100 x 10(9)/l platelets by 20 d and had peak platelet counts of greater than 400 x 10(9)/l within 40 d following chemotherapy. The peak values for circulating progenitors fell markedly after repeated courses of treatment in three of the five AML patients studied and this is likely to limit useful harvesting of such cells during later consolidation courses in this disease.

Adolescent↗
PubMed1994

Minimally differentiated acute myeloid leukaemia (AML-M0): cytochemical, immunophenotypic and cytogenetic analysis of 19 cases.

We describe our experience in the identification of 19 cases of AML-M0 categorized among 200 consecutive AML cases. Leukaemic cells from our cases were morphologically marked by agranular basophilic cytoplasm, finely dispersed chromatin and prominent nucleoli. In two cases heavily vacuolated and monocytoid-shaped blasts were also observed. Cytochemistry (MPO, SBB, alpha ANAE, alpha NBE, NASDCAE, AP, PAS) was negative in 14 cases, five cases expressing a very faint cytoplasmic positivity for alpha NBE (not exceeding 30% of the blasts) and alpha ANAE (not exceeding 41%) which was sodium fluoride resistant. In these five cases other monocytic markers (e.g. CD14) were not in favour of myelomonocytic differentiation. All the cases were anti-MPO positive at frequency > 10%. Phenotypic analysis also revealed myeloid features with all the patients having at least one myeloid antigen (CD13, CD33, CD15), Tdt was expressed in nine cases and CD7 in six cases. All cases but one were positive for CD34. Cytogenetic analysis, performed in 16 cases, showed no adequate growth in two cases and no consistent abnormality in four; among the remaining 10 cases no consistent abnormality was observed, the most common finding was trisomy 8 (two cases) and 4 (two cases) and aberrations of chromosomes 2, 3, 5, 7, 9, 12 and 21. No cases of (t9;22), Ph chromosome were observed. Interestingly three out of five patients with faint alpha NBE/alpha ANAE positivity relapsed as typical M4 (one case) or M5a (two cases).

Acute Disease↗
PubMed1995

Immunophenotype of c-kit cells in normal human bone marrow: implications for the detection of minimal residual disease in AML.

In the present study, seven normal human bone marrow samples from healthy volunteers have been analysed in order to investigate the immunophenotypic characteristics of the normal CD117+ cells and their utility for the detection of minimal residual disease in 71 acute myeloid leukaemia patients. Our results show that most of normal BM CD117+ cells coexpress the HLADR and the myeloid associated CD33 antigen. In addition, almost half of CD117+ cells are CD34+, these cells displaying a different FSC/SSC distribution when compared to the CD117+/CD34- cells. No CD117+/CD15+ and CD117+/CD10+ cells were detected and very few CD117+ cells (< 1 x 10(-3) expressing the HLADR-/CD34-, CD33+/HLADR- and CD34+/HLADR- phenotypes were found to be present in normal BM. In contrast, from the 71 AML patients analysed, 34 had CD117+/CD15+ blast cells and eight had the CD117+ phenotypes detected at low frequencies (< 1 x 10(-3)) in normal BM. In summary, the present study shows that the use of the CD117 antigen in different monoclonal antibodies combinations may be of great help for the detection of minimal residual disease in a high proportion of AML cases, especially in those patients displaying the CD117+/CD15+ phenotype, because cells coexpressing both antigens in normal BM, if present, are at very low frequencies.

Acute Disease↗
PubMed1995

Prognostic value of S-phase cells in AML patients.

Until now, reports on the cell cycle distribution of AML patients have shown highly variable results which are probably related to the technical heterogeneity of such studies. The aim of the present paper was to analyse in 204 AML patients at diagnosis the proliferative rate (assessed by the number of S-phase cells) of peripheral blood (PB) (126 cases) and bone marrow (BM) (78 cases) cells in order to explore its relationship with disease characteristics. A strong parallelism was observed regarding the relationship between the proliferative rate of the blast cells both in PB and in BM and the disease characteristics. Cases with a high proliferative rate were associated with advanced age, high WBC counts and LDH serum levels, monocytic leukaemias (assessed both by morphological and immunophenotypic criteria) and NK-associated antigens (CD56, CD16). The proliferative activity did not influence the CR rate; in contrast, cases with a high number of S-phase cells had shorter survival. In addition, multivariate analysis showed that age, the expression of CD11b, and the S-phase counts are the only three prognostic factors displaying an independent impact on survival.

Adult↗
PubMed1995

C-myc amplification, double minutes and homogenous staining regions in a case of AML.

c-myc amplification is usually associated with lymphoid malignancies and Burkitt's lymphoma in particular. We present a case of AML with c-myc amplification which was associated with homogenous staining regions (hsr) and double minutes (dmin). The administration of GCSF following induction chemotherapy resulted in a marked increase in blast numbers. The GCSF was stopped and further courses of chemotherapy given, which resulted in complete remission. The patient relapsed 7 months after diagnosis and failed to go into a second remission with reinduction therapy. We conclude that c-myc amplification is a rare event in AML, but may be associated with chemotherapy resistance and a poor prognosis, are as dmins and hsr. Growth factors should be used with caution in these patients.

Aged↗
PubMed1995

t(8;21) myelodysplasia, an early presentation of M2 AML.

The reciprocal translocation of genetic material between chromosomes 8 and 21, t(8;21), is usually restricted to cases of acute myeloid leukaemia (AML). Cases of AML with t(8;21) exhibit characteristic dysplastic features in myeloid and erythroid lineages with reduction in megakaryocytes. We report details of three patients presenting with myelodysplastic features; two had a typical t(8;21), and the third had a variant t(8;21) translocation. We discuss the significance of t(8;21) in the aetiology of myelodysplastic syndrome (MDS) and implications for the management of such patients.

Adult↗
PubMed1994

Acute myeloid leukemia with basophilic differentiation (AML, M-2B) in a cat.

A 4-year-old, neutered male Domestic Shorthair cat with a history of depression, anorexia, and weight loss was diagnosed with acute myelogenous leukemia (AML). The cat tested positive by both the feline immunodeficiency virus antibody test and feline leukemia virus enzyme-linked immunosorbent assay test. Results of cytochemical stains on peripheral blood and bone marrow specimens indicated acute myeloid leukemia with unusual basophilic differentiation (AML, M-2B).

Journal Article↗
PubMed1995

Characterization of chromosome 11 with a complex inversion and deletion in an AML [M2] using fluorescence in situ hybridization.

We report on a new case of AML [M2] where chromosome 11 was rearranged in a highly complex manner involving band 11q23. Routine G banding failed to identify the nature of this aberration which later was accomplished using whole chromosome 11-specific painting probe by the FISH technique. Chromosome 11 band q23 is frequently involved in reciprocal translocations with various chromosomes, but to have sole morbidity of such a complex nature is an atypical finding in AML [M2]. The band q23 of chromosome 11 involves the mixed lineage leukemia gene and rearrangement of this chromosomal region has been found in a variety of neoplasias. Henceforth, its precise identification has become imperative for classification of hematological malignancies and in turn to devise therapeutic strategies.

Bone Marrow↗
PubMed2002

Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations.

The receptor tyrosine kinase Flt3 is expressed and functionally important in early myeloid progenitor cells and in the majority of acute myeloid leukemia (AML) blasts. Internal tandem duplications (ITDs) in the juxtamembrane domain of the receptor occur in 25% of AML cases. Previously, we have shown that these mutations activate the receptor and induce leukemic transformation. In this study, we performed genome-wide parallel expression analyses of 32Dcl3 cells stably transfected with either wild-type or 3 different ITD isoforms of Flt3. Comparison of microarray expression analyses revealed that 767 of 6586 genes differed in expression between FLT3-WT- and FLT3-ITD-expressing cell lines. The target genes of mutationally activated Flt3 resembled more closely those of the interleukin 3 (IL-3) receptor than those of ligand-activated Flt3. The serine-threonine kinase Pim-2 was up-regulated on the mRNA and the protein level in Flt3-ITD-expressing cells. Further experiments indicated that Pim-2 function was important for clonal growth of 32D cells. Several genes repressed by the mutations were found to be involved in myeloid gene regulation. Pu.1 and C/EBPalpha, both induced by ligand-activation of wild-type Flt3, were suppressed in their expression and function by the Flt3 mutations. In conclusion, internal tandem duplication mutations of Flt3 activate transcriptional programs that partially mimic IL-3 activity. Interestingly, other parts of the transcriptional program involve novel, IL-3-independent pathways that antagonize differentiation-inducing effects of wild-type Flt3. The identification of the transcriptional program induced by ITD mutations should ease the development of specific therapies.

Acute Disease↗
PubMed2002

Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML).

The inability to undergo apoptosis is a crucial mechanism of multidrug resistance in acute myeloid leukemia (AML), and the analysis of mitochondrial apoptotic proteins may represent a significant prognostic tool to predict outcome. Bcl-2 and Bax oncoproteins were evaluated in 255 de novo AML patients (pts) by flow cytometry using an anti-bcl-2 monoclonal antibody (MoAb) and an anti-bax MoAb. The results were expressed as an index (bax/bcl-2) obtained by dividing bax mean fluorescence intensity (MFI) and bcl-2 MFI. Lower bax/bcl-2 ratio was associated with French-American-British (FAB) M0-M1 classes (P =.000 01) and CD34 more than 20% (P <.000 01). There were striking inverse correlations between CD34 or CD117 MFI and bax/bcl-2 values (r = -.40, P <.000 001 and r = -.29, P =.000 002), confirming that immaturity is consistent with this index. Moreover, lower bax/bcl-2 levels were correlated with poor-risk cytogenetics (P =.0002). A significant higher complete remission (CR) rate was found in pts with higher bax/bcl-2 levels (79% versus 45%; P =.000 01). Also, both a longer overall survival (OS) and disease-free survival (DFS) were observed in pts with higher bax/bcl-2 levels (P =.000 01 and =.019). Noteworthy, bax/bcl-2 levels accurately predicted the clinical response and outcome of pts with normal or unknown cytogenetics. Indeed, within this subset of 147 pts, higher bax/bcl-2 ratio was significantly associated both with a higher CR rate (86% versus 42%; P <.000 01) and a longer OS (P =.0016). The independent prognostic value of bax/bcl-2 ratio was confirmed in multivariate analysis. Therefore, mitochondrial oncoproteins, such as bcl-2 and bax, represent both sensitive indicators of clinical outcome and potential targets of novel proapoptotic molecules in order to circumvent chemoresistance.

Adolescent↗