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PubMed2002

Immature leukemic CD34+CXCR4+ cells from CML patients have lower integrin-dependent migration and adhesion in response to the chemokine SDF-1.

Chronic myelogenous leukemia (CML), a malignant myeloproliferative disorder originating from a pluripotent stem cell expressing the bcr-abl oncogene, is characterized by abnormal release of the expanded, malignant stem cell clone from the bone marrow (BM) into the circulation. Moreover, immature CD34+ CML cells have lower adhesion to stromal cells and fibronectin as well as lower engraftment potential in severe combined immunedeficient (SCID) and nonobese diabetic (NOD)/SCID mice than normal CD34+ cells. We report in this study that leukemic Philadelphia chromosome-positive (Ph+)CD34+ cells from newly diagnosed CML patients that express the chemokine receptor CXCR4 migrate in response to stromal-derived factor-1 (SDF-1). However, normal Ph-CD34+CXCR4+ cells derived from the same patient have significantly higher migration levels toward SDF-1. In contrast to their transwell migration potential, the SDF-1-mediated integrin-dependent polarization and migration of the Ph+CD34+CXCR4+ cells through extracellular matrix-like gels were significantly lower than for normal cells. Concomitantly, binding of these cells to vascular cell adhesion molecule-1 or fibronectin, in the presence of SDF-1, was also substantially lower. These findings suggest a major role for SDF-1-mediated, integrin-dependent BM retention of Ph+CD34+ cells.

Antigens, CD34↗

PubMed2025

Aberrant expression of MAPK1 and MCTS1 in chronic myeloid leukemia (CML).

Genomic amplification may result in aberrant gene expression and support development of cancer, including chronic myeloid leukemia (CML). In CML cell line K-562, we recently reported overexpression of TBX1 located at chromosomal position 22q11, focally co-amplified together with BCR, part of the CML hallmark fusion gene BCR::ABL1. Here, we extended that study, by identifying genomically amplified and overexpressed MAPK1/ERK2 at 22q11 together with MCTS1 at Xq22. Using pharmacological inhibitors and siRNA-mediated knockdown assays, our data collectively revealed novel regulatory connections between TBX1, MAPK1 and MCTS1, which may play a role in drug resistance.

Journal Article↗

PubMed1993

Cell biology of CML--a model linking the chronic and terminal phases.

A model for the pathogenesis of chronic myeloid leukaemia (CML) is proposed. It relies on a comparison between normal steady-state and regenerating haemopoiesis and suggests that chronic phase CML stem cells have a finite capacity for self-renewal. According to the model, metamorphosis of the disease occurs once the potential for chronic phase cell production has been exhausted. The model considers also the generation of leukocytosis in the chronic phase and the origin of the terminal phase. Comparison with normal regenerating haemopoiesis allows discrimination between features of CML that are fundamentally abnormal and those which are normally associated with regeneration.

Animals↗

PubMed1993

Cytokinetic considerations relevant to development of a successful therapeutic strategy in chronic myelogenous leukemia (CML).

Despite recent important advances in our understanding of the molecular and biological abnormalities in chronic myelogenous leukemia (CML) this new knowledge has not yet led to significant improvements in treatment. We have reviewed what is known and still unknown about some of the important properties of normal and leukemic stem cells and later progenitor cells that may be relevant to developing improved treatment strategies in the future. Clinical observations and experimental evidence strongly suggest that the major expansion of the CML population takes place in the intermediate and later maturation compartments rather than in the stem cell or early progenitor cell compartments. The expansion occurs slowly, probably taking several years to reach a trillion or more cells, at which time clinical symptoms begin to develop. The maturing leukemic progenitors do not have an increased proliferative rate, but they undergo one or more additional divisions and also live longer than comparable normal progenitors. Although no quantitative assay system is available to study the ultimate proliferative potential of human stem cells, indirect evidence suggests that the behavior of leukemic stem cells is not greatly different from that of normal stem cells. One important difference is that the leukemic stem cells (or early progenitor cells) do not curtail cell production until marrow cell densities are reached that are substantially higher than those at which normal stem cells cease production. Based on these and other considerations a possible future therapeutic strategy is suggested. Any successful treatment program for CML will probably depend on the inclusion of some type of specific drug(s) that will selectively affect leukemic progenitors.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗

PubMed1993

The German CML study, comparison of busulfan vs. hydroxyurea vs. interferon alpha and establishment of prognostic score 1.

From July 1983 to January 1991 a total of 622 patients were randomized (585 eligible) to compare the effects of hydroxyurea, interferon alpha (IFN), and busulfan on the duration of chronic phase, and survival. Further goals included the determination of prognostic parameters. 598 CML patients were documented and 575 evaluable. The Ph-status was known for 547 patients. 89.4% of the patients were Ph-positive (+). 11% had additional chromosome aberrations. The median survival of Ph+ patients by now is 4.2 years, that of Ph-patients 1.4 years. Ph-negative patients are older, tend to have lower cell counts and, as a group are more ill at diagnosis. A survival difference of about one year is expected between busulfan and hydroxyurea treated patients. Prospectively evaluated age, organomegaly related symptoms, Karnofsky index, extramedullary manifestations, number of erythroblasts and percent of circulating blasts proved to be of prognostic significance. A prognostic score (score 1) was determined which was superior to Sokal's score in the study population. 164 patients were randomized to receive IFN. In 54 patients (33%) IFN had to be terminated because of adverse effects, therapy resistance or other reasons. Clinically relevant neutralizing antibodies were detected in 9 cases. Most frequent adverse events were flu-like symptoms in 74%, gastrointestinal symptoms in 52%, and neurologic-psychiatric symptoms in 30% of patients. Reduction of the Ph-chromosome was observed in 13% of evaluable patients (10 of 75). In 4 patients complete cytogenetic remissions were observed, in three of these ongoing. Cytogenetic responders have a survival advantage. Interferon treated Philadelphia-negative CML patients have no survival disadvantage. The study is expected to allow statements as to the advantages or disadvantages of the use of busulfan, hydroxyurea and IFN in the treatment of CML as well as to the reliability of prognostic markers.

Adult↗

PubMed1993

The graft versus leukemia (GVL) effect after allogeneic bone marrow transplantation for chronic myelogenous leukemia (CML).

Immune mechanisms superimposed to the myeloablative conditioning regimens exert an additional powerful effect in eradicating leukemia and in achieving immunological control of minimal residual disease. The impact of GVHD-independent GVL has been evaluated to be absent, or near absent, in ALL, about 30% in AML and about 40% in CML. While until little time ago most of the evidence in favor of an immune antileukemia mechanism exerted by allo BMT in CML was indirect, based on the lack of GVL, there is now solid evidence of a positive type, based on the antileukemia effect of donor lymphocyte infusions in patients having relapsed after transplant. There are three lines of indirect clinical evidence for GVL in CML: they include the classical linkage between GVHD and reduced relapse rate, increased relapse rate after identical twin allografts, and increased relapse risk after effective GVHD prophylaxis, with T lymphocyte depletion in the foreground. The eradicating effects of donor lymphocyte infusions in relapsed patients are the ultimate demonstration that allogeneic immune competent cells are capable of recognizing and destroying the Ph-positive clone. However the frequency of irreversible aplasia indicates that donor lymphocytes act in the same way on residual host hematopoiesis, so that a second graft, without repeat conditioning, should be programmed for such cases.

Anemia, Aplastic↗

PubMed1993

Karyotypic conversion by interferon as preparative treatment for autologous BMT in Ph positive CML. Italian Cooperative Study Group (ICSG) on Chronic Myeloid Leukemia.

This is an interim report of the Roferon A/ABMT protocol by ICSG on CML aimed at investigating the feasibility and potential of combining treatment with alpha-IFN with ABMT in Ph+ CML. Of 675 Ph+ CML patients recruited between January 1989 and January 1991 by 44 Italian institutions, 398 were 55 or less years old and eligible for the protocol. Of 132 patients who completed IFN treatment 118 had evaluable karyotype; of these only 48 showed > 25% Ph--metaphases and were eligible for BM harvest. In 24 patients BM was collected and 13 were submitted to ABMT. The major causes of drop out from the protocol were shift to allogeneic BMT, accelerated blastic phase, patient refusal and logistic problems. Data on hematologic reconstitution are presently available in 11 patients: Neutrophils were > 0.5 x 10(9)/l in 23 days (median), (range 16-40 days); platelets reached 50 x 10(9)/l in 28 days (median), (range 25-100 days). One patient had a very delayed BM take and was rescued with autologous peripheral blood stem cells collected at diagnosis.

Adult↗

PubMed1998

Granulocytic sarcoma as isolated extramedullary relapse after donor lymphocyte infusion in a patient with CML who relapsed after allogeneic bone marrow transplantation: a case report.

Isolated granulocytic sarcoma (GS) has rarely been reported in a patient who underwent allogeneic bone marrow transplantation (BMT) for chronic myelogenous leukemia (CML). We report here a patient who developed an isolated GS after achieving hematologic and cytogenetic remission by donor lymphocyte infusion for the relapse of CML following BMT. The size of GS was slightly decreased after local irradiation of 1,500 cGy without further systemic chemotherapy or immunotherapy. He remained in hematologic and cytogenetic remission without systemic relapse of CML for 8 months. Thereafter, he died of sepsis. The appropriate treatment of GS and impact of its occurrence on prognosis following allogeneic BMT has yet to be determined.

Bone Marrow Transplantation↗

PubMed2006

[Detection of bcr/abl fusion gene from K562 cell line and mononuclear cells of CML patients by DNA-PCR].

OBJECTIVE: To detect bcr/abl fusion gene at DNA level in K562 cell line and mononuclear cells from patients with chronic myelogenous leukemia (CML). METHODS: Based on previous research, a set of DNA-PCR primers was redesigned. DNA from K562 cells and mononuclear cells of CML patients was extracted respectively. After DNA-PCR for bcr/abl fusion gene the amplified fragments were then sequenced. RESULT: At DNA level the bcr/abl fusion gene in K562 cells and mononuclear cells of 2 CML patients was amplified. Furthermore, the DNA breakpoint of fusion gene in the above samples through sequencing of amplified fragments was localized. CONCLUSION: DNA-PCR offers a new detection technology for bcr/abl fusion without the expression of fusion gene.

Fusion Proteins, bcr-abl↗

PubMed2004

Comparison of genetic changes between interphase and metaphase nuclei in monitoring CML and APL treatment using DC-FISH technique.

In leukemias, the monitoring techniques on the response after the treatment have clinical importance for evaluating new therapeutic approaches and identifying the risk of relapse. In this study, genetic changes before and after chemotherapy in interphase and metaphase nuclei of bone morrow of adults with provisional diagnosis of leukemia were compared to understand the molecular characterization and pathogenesis of the leukemia for the classification of diagnosis and prognosis. We examined bone morrow cells of 47 chronic myeloid leukemia (CML) cases (29 of 47 at the time of diagnosis, 31 of 47 after chemotherapy) with the bcr/abl translocation probes and of 10 acute promyelocytic leukemia (APL) cases (7 of 10 at the time of diagnosis, 4 of 10 after chemotherapy) with the PML/RARalpha translocation probes by using dual color-flourescence in situ hybridization (DC-FISH). For each case, 400 interphase nuclei and 11 to 25 metaphases nuclei were analysed. The ratios of translocations before and after chemotherapy were compared between interphase and metaphase nuclei. After chemotherapy, though, translocations were detected in interphase nuclei of 29 of the 31 CML and 4 of the 4 APL cases, these translocations were determined in metaphase nuclei of only 14 of the 31 CML and 1 of the 4 APL cases with very low ratios (p < 0.01). The results showed that the rates of translocation positive interphase nuclei were higher than the rates of translocation positive metaphase nuclei (p < 0.01) after chemotherapy, so there may be some factors effecting proliferative activity of metaphase formation in leukemias.

Bone Marrow Cells↗

PubMed1999

[Interferon alfa-2b treatment of adult patients during early chronic phase of Ph1-positive chronic myeloid leukemia (initial report on a cooperative study, protocol CML-MIG-97)].

AIM: Evaluation of clinical effectiveness of two regimens of induction therapy of an early chronic stage of Ph'-positive chronic myeloid leukemia including interferon-alpha 2b (intron-A, "Schering Plough") in a cooperative randomised trial on the protocol CML MIG-97. MATERIALS AND METHODS: 42 patients with chronic myeloid leukemia were treated either with intron-A in standard doses (5 IU/m2/day) alone or in combination with monthly 10-day courses of low-dose cytosine-arabinoside (10 mg/m2/twice a day). The effect was assessed by the international criteria of a complete and partial hematologic remission and the cytogenetic response. RESULTS: Intron-A therapy in standard doses produced a pronounced cytogenetic response in 28.6% of the patients. In low-dose interferon-alpha-2b (reaferon and intron-A, 1-3 IU/m2/day) in combination with various regimens of chemotherapy only minimal cytogenetic response was achieved. CONCLUSION: A pronounced cytogenetic response in early chronic stage of CML to standard doses of intron A holds promise in prolongation of CML patients survival and design of new effective therapy programs.

Adjuvants, Immunologic↗

PubMedDate not supplied

GST-pi expression in BCR-ABL+ and BCR-ABL- cells from CML patients.

Our laboratory has been involved in the study of glutathione-sulfhydryl-transferase-pi (GST-pi) for several years. We have recently observed that during haematopoiesis in BMSC liquid cultures from CML patients who were candidates for transplant GST-pi was expressed in presumably malignant cells during different stages of cellular maturation. To confirm this finding, in the present work we are detecting GST-pi expression by immunofluorescence in BCR-ABL+ and BCR-ABL- cells done by FISH of PB from 30 CML patients during different clinical status: treatment (T), hematological relapse (R), blastic crisis (BC) or post-allotrasplant (PT). As well as in PB from 30 Blood-Bank donors. The results were %BCR-ABL+ GST-pi+ cells: T = 1-67, R = 33-69, BC = 90-100 and PT = 1-2; %BCR-ABL- GST-pi+ cells: T = 2-31, R = 5-18, BC = 0-10 and PT = 2-5; %BCR-ABL- GST-pi- cells: T = 2-97, R = 13-62, BC = 0 and PT = 93-96; %BCR-ABL+ GST-pi- cells: T = 0, R = 0, BC = 0 and PT = 0. GST-pi was not expressed in donor cells. The results obtained confirm our previous observations and suggest that GST-pi expression might be used for the evaluation of the minimal residual disease in CML patients.

Adolescent↗

PubMed1999

[Chromosomal abnormalities in 38 CML cases of various phases].

OBJECTIVE: To study the genomic abnormality underlying the blast crisis of chronic myeloid leukemia(CML). METHODS: 15 CML patients in blast crisis (BC), 3 in accelerated phase (AP) and 20 in chronic phase (CP) were analyzed by conventional cytogentics, comparative genomic hybridization (CGH) and dual color chromosomal painting. RESULTS: Philadelphia (Ph) chromosome was identified in every case studied. Only 5 among 20 CP patients had additional abnormalities while 12 out of 14 patients with disease progression (BC + AP) showed extra numerical and/or structural chromosmal aberrations. Cytogenetically, the most common chromosome gains during BC and AP were double or triple Ph chromosome(5/14), trisomy 8(5/14), trisomy 7(1/14) and 17 (1/14). Three cases showed the same region being involved in translocations t(1;17)(q12-21;q10), t(1;10) (q12-21;q26) and t(1;11)(q12-21;p15). CGH analysis detected genetic imbalances in 8 cases. In one case, a very complex chromosmal translocation del(3), del(6)(q13-21), der(6)t(17;3;6), der(17)t(6;17) was characterized by chromosomal painting. CONCLUSION: We find that the combined use of CGH, chromosomal painting, and classic cytogenetic analysis allows a better evaluation of the genomic aberration involved in CML blastic transformation, and offers new directions for its further molecular investigation.

Adult↗

PubMed2001

[Experimental systems in CML biology].

It has been established that the BCR-ABL oncogene produced on the Philadelphia chromosome in human chronic myeloid leukemia(CML) directly causes leukemic transformation of multipotential progenitor cells. In order to study the molecular basis of this process, many convenient and useful biological assays have been found, including transformation of mouse bone marrow cells in primary culture and of Rat1 fibroblasts, cytokine-independent growth of dependent cell lines, retrovirus-mediated murine CML model, and transgenic mice model. New biological activities such as anti-apoptosis, anti-DNA repair, differentiation of ES cells may further give supportive explanations for clinical manifestation of CML. NOD/SCID transplantation model and conditional transgenic model may be the current best animal system by which to investigate cell dynamics in the most strict and natural circumstances.

Animals↗

PubMed2001

[Radiation-related CML].

The clinical, cytogenetic and molecular-genetic findings of 55 patients with radiation related chronic myelocytic leukemia(CML) among the Hiroshima atomic bomb survivors were compared with 167 CML patients without a history of the radiation exposure. The retrospective analysis of the hematological data kept at the laboratory center where the survivors had been examined twice a year revealed a possible chronologic sequence in appearance of clinical and laboratory findings characteristic of CML. No particular differences were observed between the two groups in the incidence of Philadelphia chromosome and break points of the BCR gene, contrasting with those of radiation-related acute myelocytic leukemia which showed complex chromosome abnormalities without specific type of translocations, especially of 8;21 and 15;17, and a high incidence of genetic instability of the leukemic cells.

Genes, abl↗

PubMed2001

[Autologous bone marrow transplantation for CML].

The first line therapy for CML is IFN-alpha and/or allogeneic hematopoietic stem cell transplantation(HSCT). The indication of autologous HSCT is limited for patients with no HLA-matched donor, and is recognized as an experimental therapy. Major problems of autologous HSCT for CML are contamination of Ph1-positive cells to graft and no GVL effects. To concur these problems, many attempts have been made such as the collection of peripheral blood stem cells after high dose chemotherapy, ex vivo purging using antisense, administration cyclosporin to induce GVL effect, and post-HSCT therapy by IFN-alpha +/- Interleukin-2. Autologous HSCT for CML is still to be a hopeful candidate for pursuing cure.

Bone Marrow Purging↗

PubMed2001

[Therapeutic application for the aged with CML].

Therapeutic application for elderly CML patients had been restricted to use of alkylating or antimetabolite agents. In order to improve quality of life in the aged with CML interferon-alpha therapy is now first choice for treatment of elderly chronic phase of CML patients under appropriate informed consent. This treatment provided long term survival with cytological and cytogenetic responses even in the aged. In elderly patients attention has to be paid for the occurrence of side effects such as psychological changes. Further studies are on going in special reference to molecularly targeted therapy, i.e. a specific inhibitor of tyrosine kinase, or non-myeloablative stem cell transplantation.

Aged↗

PubMed2000

[Influence of IFN-alpha and IFN-alpha combined with GM-CSF on expression of the genes related to cell apoptosis of MNCs from bone marrow in CML patients].

OBJECTIVE: To investigate the effects of interferon-alpha(IFN-alpha) and IFN-alpha combined with granulocytic macrophage colony-stimulating factor(GM-CSF) on expression of bcr-abl, bcl-2 and c-myc genes in the mononuclear cells(MNCs) from bone marrow(BM) of the patients with chronic myelogenous leukemia at chronic phase(CML-CP). METHODS: The MNCs were collected from bone marrow of 14 CML-CP patients by centrifugalization in lymphocyte-separation medium, and cultivated in the medium with IFN-alpha and IFN-alpha plus GM-CSF for 24 hours. The expression levels of bcr-abl, bcl-2, c-myc and beta-actin were detected by using relatively quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and optical density scanning technology for the amplified fragments. The statistical differences between each inducing experimental group and the control were analyzed by t-test in pairs. RESULTS: Both IFN-alpha (200 U.ml-1) and IFN-alpha combined with GM-CSF (10 ng.ml-1) significantly inhibited bcr-abl gene expression, meanwhile IFN-alpha partially suppressed c-myc and bcl-2 gene expression, and GM-CSF significantly inhibited bcl-2 gene expression but partially upregulated bcr-abl and c-myc gene expression levels on the basis of IFN-alpha effects. CONCLUSIONS: Both IFN-alpha and IFN-alpha plus GM-CSF can inhibit the expression of anti-apoptosis gene such as bcr-abl and bcl-2, and regulate the expression of c-myc. It is the possible mechanism of IFN-alpha therapy or combined therapy on CML at chronic phase that the malignant clone expansion is inhibited by promoting apoptotic cell death.

Bone Marrow Cells↗