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PubMed2006

A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation.

The oncogenic kinase Bcr-Abl is thought to cause chronic myelogenous leukemia (CML) by altering the transcription of specific genes with growth- and survival-promoting functions. Recently, Bcr-Abl has also been shown to activate an important regulator of protein synthesis, the mammalian target of rapamycin (mTOR), which suggests that dysregulated translation may also contribute to CML pathogenesis. In this study, we found that both Bcr-Abl and the rapamycin-sensitive mTORC1 complex contribute to the phosphorylation (inactivation) of 4E-BP1, an inhibitor of the eIF4E translation initiation factor. Experiments with rapamycin and the Bcr-Abl inhibitor, imatinib mesylate, in Bcr-Abl-expressing cell lines and primary CML cells indicated that Bcr-Abl and mTORC1 induced formation of the translation initiation complex, eIF4F. This was characterized by reduced 4E-BP1 binding and increased eIF4G binding to eIF4E, two events that lead to the assembly of eIF4F. One target transcript is cyclin D3, which is regulated in Bcr-Abl-expressing cells by both Bcr-Abl and mTORC1 in a translational manner. In addition, the combination of imatinib and rapamycin was found to act synergistically against committed CML progenitors from chronic and blast phase patients. These experiments establish a novel mechanism of action for Bcr-Abl, and they provide insights into the modes of action of imatinib mesylate and rapamycin in treatment of CML. They also suggest that aberrant cap-dependent mRNA translation may be a therapeutic target in Bcr-Abl-driven malignancies.

Adaptor Proteins, Signal Transducing↗

PubMed1999

Characterization of 12p molecular events outside ETV6 in complex karyotypes of acute myeloid malignancies.

Acute myeloid disorders with rearrangements of 12p outside the ETV6 gene were characterized by fluorescence in situ hybridization (FISH) with a panel of DNA probes. Seven patients with de novo acute myeloid leukaemia (AML), one with secondary acute myeloid leukaemia (sAML), and one in the blast phase of chronic myeloid leukaemia (CML-BP) were enrolled in the study. All AML cases showed multiple karyotypic changes. Chromosome 5 and/or 7 deletions were the most frequent accompanying changes. FISH revealed amplification, cryptic translocation, and fragmentation of chromosome 12, not discernible at karyotypic level. Different karyotypic rearrangements of 12p showed a common molecular event. Among the seven cases in which breakpoints could be determined, six were telomeric and one centromeric to ETV6. In three AML cases a new recurrent breakpoint in the telomeric region was identified distally to locus D12S158 and to pac 922B22 which is the most telomeric probe available for 12p. Accompanying cryptic deletions were also detected in five patients and the commonly deleted region, of around 700 kb, included the ETV6 gene and the D12S391 locus.

Adult↗

PubMed1997

Chemotherapy-induced acral erythema in leukemic patients: a report of 15 cases.

BACKGROUND: Chemotherapy-induced acral erythema is a distinct localized cutaneous response to certain systemic chemotherapeutic agents. METHODS: Between January 1990 and December 1994, from a total of 76 leukemic patients who have received combination chemotherapy consisting of cytosine arabinoside and anthracycline antibiotics, 15 patients developed chemotherapy-induced acral erythema. Fourteen of the patients had acute myelocytic leukemia, and one of them had chronic myelogenous leukemia in blast phase. Clinical features of these 15 patients have been analysed. Biopsy specimens obtained from eight of the patients were also evaluated for histopathologic alterations. RESULTS: The overall incidence of this reaction was found to be 19.7% in our group of patients receiving this chemotherapy protocol. The onset of reaction varied from the fourth to the seventeenth days of the chemotherapy and resolved within 2 weeks in most of the patients. Lesions appeared as well-defined erythema and edema involving the palmar surfaces in all of the patients. In nine of the patients the reaction recurred with subsequent chemotherapies. Scattered necrotic keratinocytes, vacuolar alterations of the basal layer, and mild to moderate perivascular lymphocytic infiltration in the dermis were the histopathologic findings observed in the biopsy specimens. CONCLUSIONS: Chemotherapy-induced acral erythema is a frequent reaction in patients who are receiving high-dose chemotherapy. For patients in whom this self-limited condition develops, reassurance is the mainstay of therapy. Awareness of this reaction is also important to be able to differentiate it from acute graft versus host disease in patients who receive bone marrow transplants.

Adolescent↗

PubMed1979

[Pseudo-hyperkalaemia in myeloproliferative diseases (author's transl)].

In two patients in the blast phase of chronic myeloid leukaemia there was a marked rise in serum potassium levels, while plasma potassium was at the lower range of normal and there were no signs of hyperkalaemia clinically. After reduction of the pathological cells under cytostatic treatment the serum potassium levels returned to normal. This in-vitro phenomenon seems to be more common in patients with marked thrombocytosis and leukaemia than has previously been thought. In such patients hypokalaemia may be undetected because serum potassium levels arenormal. Pseudo-hyperkalaemia exists when the potassium level is normal in plasma obtained by centrifugation immediately after the blood sample has been taken, without addition of plastic spheres and at once separated from the blood cells.

Adult↗

PubMed1995

Overexpression of DR-nm23, a protein encoded by a member of the nm23 gene family, inhibits granulocyte differentiation and induces apoptosis in 32Dc13 myeloid cells.

Chronic myelogenous leukemia evolves in two clinically distinct stages: a chronic and a blast crisis phase. The molecular changes associated with chronic phase to blast crisis transition are largely unknown. We have identified a cDNA clone, DR-nm23, differentially expressed in a blast-crisis cDNA library, which has approximately 70% sequence similarity to the putative metastatic suppressor genes, nm23-H1 and nm23-H2. The deduced amino acid sequence similarity to the proteins encoded by these two latter genes is approximately 65% and includes domains and amino acid residues (the leucine zipper-like and the RGD domain, a serine and a histidine residue in the NH2- and in the COOH-terminal portion of the protein, respectively) postulated to be important for nm23 function. DR-nm23 mRNA is preferentially expressed at early stages of myeloid differentiation of highly purified CD34+ cells. Its constitutive expression in the myeloid precursor 32Dc13 cell line, which is growth-factor dependent for both proliferation and differentiation, results in inhibition of granulocytic differentiation induced by granulocyte colony-stimulating factor and causes apoptotic cell death. These results are consistent with a role for DR-nm23 in normal hematopoiesis and raise the possibility that its overexpression contributes to differentiation arrest, a feature of blastic transformation in chronic myelogenous leukemia.

Amino Acid Sequence↗

PubMed2002

Efficacy and safety of gemtuzumab ozogamicin in patients with poor-prognosis acute myeloid leukemia.

The objective of this work was to determine the safety and efficacy of gemtuzumab ozogamicin in patients with poor prognosis acute myeloid leukemia (AML). Patients with the following diagnoses/characteristics were treated with 1-3 infusions of gemtuzumab ozogamicin at a dose of 9 mg/m2: (1) relapse of AML < or = 6 months of first complete remission (CR); (2) AML refractory to chemotherapy at initial induction or at first relapse; (3) AML in second or greater relapse; (4) myeloid blast crisis of chronic myeloid leukemia (CML); (5) untreated patients > or = 70 years or > or = 55 years with abnormal cytogenetics (excluding inv 16, t(15;17) and t(8;21)) and/or an antecedent hematologic disorder; (6) refractory anemia with excess blasts in transformation (RAEBT). Forty-three patients, ages 19-84 (mean 62), were treated, including 7 patients with untreated AML age > 70 years, 2 with untreated RAEBT, 14 with AML first salvage (first remission 0-6 months), 15 with AML > or = second salvage and 14 with myeloid blast phase of CML. The overall response rate was 14%, with 4/43 (9%) patients achieving CR and 2/43 (5%) achieving CR without platelet recovery. The most significant toxicity was neutropenic fever, which occurred in 84% of patients. In conclusion, in patients with relapsed/refractory AML, gemtuzumab ozogamicin has a comparable response rate to single-agent chemotherapy and may offer a more favorable toxicity profile.

Acute Disease↗

PubMed2003

Donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukaemia.

The understanding of the use of donor lymphocyte infusions (DLI) for graft-versus-leukaemia (GVL) in the treatment of chronic myeloid leukaemia (CML) post haemopoietic stem cell transplant (HSCT) has advanced during the last years. In relapsed leukaemia post-stem cell transplant, DLI can achieve durable remissions in 60-73% patients. Technical improvements in molecular methods of detection of the BCR-ABL transcripts permit the prediction of relapse with increased sensitivity and reproducibility. Use of DLI early at relapse is important since responses to DLI are less likely in the face of bulky or blast-phase disease. Exogenous interleukin-2 may enhance the response to DLI but total cell dose is also relevant to the efficacy of DLI with the effective cell dose (ECD) required being lower in HLA matched unrelated DLI donors compared to siblings. Donor T-lymphocytes target minor histocompatibility (H) antigens and the relative tissue distribution of these may influence the toxicity of DLI, which includes graft-versus-host-disease (GVHD). Modified methods of delivery such as selective deletion of CD8+ cells or escalating cell dosage regimens have reduced the incidence of serious morbidity due to GVHD without compromising the GVL effect mediated by DLI. These approaches have not removed the risk of GVHD entirely and conditional suicide protocols utilising the HSV-tk or fas receptor derived genes are being developed in the clinic. Since significant morbidity and mortality is attributable to the conditioning regimen used prior to HSCT, awareness of the potency of DLI has driven the development of reduced intensity conditioning (RIC) regimens. The purpose of RIC is to enhance tolerisation of the host to the graft while permitting the establishment of donor haemopoiesis. DLI may then be used subsequently to enhance the GVL effect.

Hematopoietic Stem Cell Transplantation↗

PubMed2003

Aminopeptidase inhibitors inhibit proliferation and induce apoptosis of K562 and STI571-resistant K562 cell lines through the MAPK and GSK-3beta pathways.

A tyrosine kinase inhibitor, STI571, has been demonstrated to be effective for the treatment of chronic myelogenous leukemia (CML). STI571 inhibits tyrosine kinase activity of ABL and induces apoptosis of CML cells. However, drug resistance develops commonly in patients with blast phase CML, and has become a significant therapeutic problem. We examined the effects of aminopeptidase inhibitors on CML cell line (K562) and a STI571-resistant subline of K562. Ubenimex and the more potent aminopeptidase inhibitor, actinonin, inhibited proliferation of both K562 cells and STI571-resistant K562 cells and also induced their apoptosis in dose- and time-dependent manners. Ubenimex and actinonin induced the activation of caspase-3, and the induction of apoptosis was inhibited by pan-caspase inhibitor, indicating this apoptosis is caspase-dependent. We found that serine phosphorylation of both MAPK and glycogen synthase kinase-3beta were suppressed by aminopeptidase inhibitors in parent K562 and STI571-resistant K562 cells. The expression level of cyclin D1 protein was also reduced by ubenimex and actinonin in both cell lines. These results indicated STI571-resistance does not confer the cross-resistance to aminopeptidase inhibitors in K562 cells and revealed the new findings of aminopeptidase inhibitor-induced intracellular signaling pathways.

Aminopeptidases↗

PubMed1988

Chromosomal location of the genes encoding the leukocyte adhesion receptors LFA-1, Mac-1 and p150,95. Identification of a gene cluster involved in cell adhesion.

The adhesion receptors Mac-1, LFA-1, and p150,95 are cell surface alpha/beta heterodimers that play a key role in leukocyte adhesion processes. The genes for Mac-1, LFA-1, and p150,95 alpha subunits have been located to chromosome 16 by means of Southern blot analysis using a series of somatic cell hybrids. Chromosomal in situ hybridization has demonstrated that the genes for the three alpha subunits map to the short arm of chromosome 16, between bands p11 and p13.1, defining a cluster of genes involved in leukocyte adhesion. The gene encoding the LFA-1/Mac-1/p150,95 beta subunit, and defective in leukocyte adhesion deficiency, has been located on chromosome 21, band q22. The leukocyte adhesion receptor alpha and beta subunits are mapped to chromosomal regions that have been shown to be involved in cytogenetic rearrangements in certain patients with acute myelomonocytic leukemia and the blast phase of chronic myelogenous leukemia, respectively.

Animals↗

PubMed2006

Allogeneic haematopoietic cell transplantation for chronic myelogenous leukaemia in the era of imatinib: a retrospective multicentre study.

OBJECTIVE: To analyse the results of allogeneic haematopoietic cell transplantation (HCT) in patients with advanced stages of Philadelphia chromosome-positive chronic myelogenous leukaemia (CML) who had previously been treated with imatinib mesylate (IM). METHODS: We analysed the outcome of 61 patients with CML who had received allogeneic HCT from sibling (n = 18) or unrelated (n = 43) donors after having been treated with IM. Forty-one patients had received IM because of accelerated or blast phase CML. Conditioning therapy contained standard doses of busulfan (n = 25) or total-body irradiation (n = 20) in conjunction with cyclophosphamide in the majority of cases. Sixteen patients received dose-reduced conditioning with fludarabine-based regimens. RESULTS: The incidence of grades II-IV and III-IV graft-versus-host disease was 66% and 38% respectively. The probability of overall survival (OS), disease-free survival (DFS) and relapse at 18 months for the whole patient cohort were 37%, 33% and 24% respectively. The probability of non-relapse mortality (NRM) at 100 d and 12 months was 30% and 46% respectively. Univariate analysis showed that fludarabine-based conditioning therapy, age > or = 40 yr and >12 months interval between diagnosis and transplantation were associated with a significantly lower OS and DFS and a higher NRM. CONCLUSION: These data suggest that although pretreatment with IM is not an independent negative prognostic factor, it cannot improve the dismal prognosis of CML patients at high risk for transplant-related mortality.

Adolescent↗

PubMed1989

HRAS1 and INS genes are relocated but not structurally altered as a result of the t(7;11)(p15;p15) in a clone from a patient with acute myeloid leukaemia (M4).

A patient whose leukaemic cells carried the rare t(7;11)(p15;p15) was diagnosed as having acute myelomonocytic leukaemia (AML-M4), and supports the association of this specific translocation with forms of acute myeloid leukaemia showing differentiation. Blast phase chronic myeloid leukaemia was excluded by lack of involvement of the ABL and BCR genes. Chromosome in situ hybridization studies showed that both the HRAS1 and INS genes were present on the terminal part of chromosome 11p which was translocated to chromosome 7p. Neither HRAS1 nor INS were structurally rearranged. Field inversion gel electrophoresis showed that a 400 kb fragment encompassing HRAS1 was structurally entire in leukaemic DNA. Because the INS gene, which was also translocated, is probably located proximal to HRAS1 on chromosome 11p, it is unlikely that HRAS1 was near the chromosome 11 breakpoint or involved in this leukaemia.

Cells, Cultured↗

PubMed1993

Clinical, haematological and cytogenetic features in 24 patients with structural rearrangements of the Q arm of chromosome 3.

To determine the frequency and clinical significance of acquired abnormalities of chromosome 3 at q21 and q25-26 in haematological malignancy, we reviewed the haematological and cytogenetic features of 24 patients with a 3q rearrangement identified amongst 1200 cases with clonal cytogenetic abnormalities detected at our institutions during a 12-year period. Thirteen patients presented with de novo acute myeloid leukaemia (AML), 10 with myelodysplasia (MDS) and one in blast phase of chronic myelogenous leukaemia. Twenty patients (83%) had megakaryocytic dysplasia and 14 (58%) had normal or increased numbers of megakaryocytes, but only four patients (16%) had absolute thrombocytosis > 500 x 10(9)/l (three with AML, one with MDS transforming to AML). A review of 205 cases of AML investigated in our institutions between 1985 and 1990 for whom cytogenetic results were obtained revealed that a platelet count > 500 x 10(9)/l at presentation was highly suggestive of an underlying 3q abnormality. A limited review of the literature on this subject confirmed that 15-20% of patients with a 3q abnormality will have thrombocytosis. The response of these patients to conventional antileukaemic therapy is uniformly poor, despite haematological and clinical differences between the subtypes of 3q rearrangements.

Acute Disease↗

PubMed1995

A correlation between the expression of the bcr-abl chimeric gene and severity of the clinical state of CML patients with time.

Using the reverse polymerase chain reaction, four Ph' positive CML patients were followed for 2 years; a correlation between the severity of the clinical state and the b3a2 expression was noted with time. Additionally, amplification of the c-myc proto-oncogene was observed, using Southern blot analysis, in one patient prior to his entry to the blast phase. No reorganization of the bcr-abl rearrangement site was found in the latter patient. The data suggest that a routine follow-up of CML patients using the Southern blot analysis and the reverse transcription-polymerase chain reaction might be of importance in evaluating the progression of the disease.

Adult↗

PubMed2005

Distinguishing between proliferating nodal lymphoid blasts in chronic myelogenous leukemia and non-Hodgkin lymphoma: report of three cases and detection of a bcr/abl fusion signal by single-cell analysis.

Lymph node biopsies were analyzed from three patients with chronic myelogenous leukemia (CML) showing nodal blast proliferation. Immunohistochemically, the blasts from all three patients had an immature marker profile with a T-blast population (cCD3+, CD4-, CD7+, CD8-, CD99+, terminal deoxynucleotidyl transferase +) and a hematopoietic progenitor cell marker (CD34). In two patients, the blasts also expressed myeloid lineage specificity (naphthol AS-D chloroacetate esterase activity and myeloperoxidase positivity). However, it was difficult to distinguish between blast proliferation in CML and non-Hodgkin lymphoma from these immunohistopathological findings alone. Subsequently, bcr gene rearrangement and bcr/abl mRNA expression were detected by Southern blot and reverse transcription-polymerase chain reaction analysis of the lymph nodes. Fluorescence in situ hybridization (FISH) analysis of lymph node touch smears also disclosed bcr/abl gene fusion signals in the blasts of all patients, confirming that the blasts were derived from Philadelphia chromosome-positive CML. Accurate discrimination between the proliferating nodal blasts of CML and non-Hodgkin lymphoma is essential for determining subsequent therapy. FISH analysis of bcr/abl in single-cell blast preparations is an efficient tool that allows rapid, accurate cytopathological diagnosis of extramedullary blast-phase CML and its discrimination from non-Hodgkin lymphoma.

12E7 Antigen↗

PubMed2006

Targeted degradation of the AML1/MDS1/EVI1 oncoprotein by arsenic trioxide.

Arsenic trioxide (ATO) has been found to be an effective treatment for acute promyelocytic leukemia patients and is being tested for treating other hematologic malignancies. We have previously shown that AML1/MDS1/EVI1 (AME), a fusion gene generated by a t(3;21)(q26;q22) translocation found in patients with chronic myelogenous leukemia during blast phase, myelodysplastic syndrome, or acute myelogenous leukemia (AML), impairs hematopoiesis and eventually induces an AML in mice. Both fusion partners of AME, AML1 and MDS1/EVI1, encode transcription factors and are also targets of a variety of genetic abnormalities in human hematologic malignancies. In addition, aberrant expression of ectopic viral integration site 1 (EVI1) has also been found in solid tumors, such as ovarian and colon cancers. In this study, we examined whether ATO could target AME and related oncoproteins. We found that ATO used at therapeutic levels degrades AME. The ATO treatment induces differentiation and apoptosis in AME leukemic cells in vitro as well as reduces tumor load and increases the survival of mice transplanted with these cells. We further found that ATO targets AME via both myelodysplastic syndrome 1 (MDS1) and EVI1 moieties and degrades EVI1 via the ubiquitin-proteasome pathway and MDS1 in a proteasome-independent manner. Our results suggest that ATO could be used as a part of targeted therapy for AME-, AML1/MDS1-, MDS1/EVI1-, and EVI1-positive human cancers.

Animals↗

PubMed2006

Immunophenotypic characterization of peripheral blast cells in a leukemic miniature pig.

The health status of a 4-year-old female, dd-haplotype miniature pig deteriorated rapidly, so the animal finally had to be euthanized because of poor clinical condition. Necropsy revealed a massive leukocytic infiltration in the parenchymatous organs of the abdominal cavity. On hematologic cell counting, severe leukocytosis (69.3 x 10(9) cells/liter) and high-grade basophilia (6.9 x 10(9) cells/liter) were evident. Cytologic examination, as well as analysis of expression of leukocyte differentiation antigens by means of flow cytometry, classified blasts, which accounted for about 22% of leukocytes, as biphenotypic cells co-expressing the myeloid marker SWC3 (CD172a) and the lymphoid markers CD5 and CD25. Hematologic features resembled those seen in humans with chronic myeloid leukemia at blast phase.

Animals↗

PubMed2002

Multifaceted approach to the treatment of bcr-abl-positive leukemias.

Bcr-Abl-positive leukemias include chronic myelogenous leukemia (CML), both myeloid and lymphoid blast-phase CML, and some cases of acute lymphoblastic leukemia. The chimeric bcr-abl gene codes for a tyrosine kinase that is constitutively activated in the leukemic cells and plays the central role in leukemogenesis. Hematologic malignancies, including Bcr-Abl-positive leukemias, also frequently have overactivity of the Ras signaling pathway, leading to abnormal transduction of growth and survival signals. New and investigational therapeutic options that target these specific molecular defects of leukemic cells include the tyrosine kinase inhibitor imatinib mesylate (STI571) and farnesyltransferase inhibitors (R115777, SCH66336), which block localization of Ras proteins to the cell membrane. While single-agent therapy with these new agents may produce hematologic and cytogenetic remissions in patients with Bcr-Abl-positive leukemias, molecular remissions are less common, and resistance may develop. Therefore, the development of a multifaceted therapeutic approach to these leukemias is of great interest. Arsenic trioxide (ATO), which has significant activity in patients with relapsed and refractory acute promyelocytic leukemia, is a potential addition to the therapeutic arsenal. While some of the molecular activities of ATO are specific to acute promyelocytic leukemia, arsenicals also have a broad variety of antineoplastic properties that may be useful in combination therapy with agents that target specific molecular defects of Bcr-Abl-positive leukemias.

Alkyl and Aryl Transferases↗

PubMed2000

Light microscopic detection of BCR-ABL transcripts after in-cell RT-PCR: fusion gene expression might correlate with clinical evolution of chronic myeloid leukemia.

A procedure for in-cell amplification of the hybrid BCR-ABL mRNA by reverse transcription and polymerase chain reaction (RT-PCR) without extraction of the nucleic acids was performed directly in fixed and permeabilized cells of leukemia patients (22 patients with Ph'-positive chronic myeloid leukaemia-CML and 1 with Ph'-positive acute leukaemia-AL, as well as 7 Ph'-negative cases) and Ph'-positive human leukaemia cell lines (K562, LAMA-84, BV173). The labelling of the amplified sequences was done employing biotinylated primers and a second PCR in a semi-nested fashion with a low number of cycles. An enzymatic system based on biotin-streptavidin-chromogen reaction was used for the detection of labeled PCR product, thus producing a coloured product, visible to the eye under a standard light microscope. All samples from patients with cytogenetic and molecular evidence of BCR-ABL rearrangement showed specific cytoplasmic staining at the site of the amplified hybrid transcripts. It allowed definite distinction between positive and negative cells. K562, LAMA-84, BV173 cells were characterized with strong diffuse staining while an interesting finding of the present study was the presence of variable quantities of colour product in patients' samples which might be due to different mRNA expression. Early and intermediate stages of myeloid maturation showed more intense reactivity. Cases with an aggressive course of accelerated or blast phase CML and AL were found to have a considerable subset of cells with strongly expressed signal while cases in chronic phase were characterised with uniform weak to moderate reaction. Our observations support the hypothesis that the amount of BCR-ABL transcript expression within neoplastic cells may play a role in dictating the eventual behaviour of the leukaemic clone. Future studies at a single cell level of larger series of consecutive cases with a follow up might be able to identify those patients who are prone to transformation and provide certain indications for further therapeutic decisions.

Adolescent↗