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PubMed1979

Chronic myelocytic leukemia (CML): failure to detect residual normal committed stem cells in vitro.

Granulocytic colonies grown in culture from marrow and peripheral blood from five patients with Ph1-positive CML and heterozygous at the G-6-PD locus were analyzed for G-6-PD in order to identify CFU-C that do not arise from the CML clone. The patients had both B and A enzymes in normal tissues, but their CML clones typed as B. Whereas about 50% of colonies from normal subjects heterozygous as the G-6-PD locus show type-A G-6-PD and 50% type B, only two of the 1308 colonies from the CML patients had type-A G-6-PD. These data provide little evidence for persistence of normal committed stem cells in CML, a finding in contrast to that made previously in polycythemia vera, another clonal stem cell myeloproliferative disorder.

Adult↗

PubMed1987

Heterogeneity in expression of the bcr-abl fusion transcript in CML blast crisis.

The 9;22 Philadelphia chromosome translocation in chronic myelogenous leukemia (CML) generates a bcr-abl fusion gene which codes for an aberrant 8-kb bcr-abl hybrid message. CML blast crisis cell lines display enhanced in vitro expression of this aberrant bcr-abl transcript when compared with fresh CML chronic phase cells. We directly compared in fresh patient samples the level of expression of the bcr-abl transcript in CML blast crisis versus chronic phase cells. All chronic phase patients displayed relatively low amounts of this aberrant transcript, while four of 10 blast crisis patients expressed this transcript at significantly higher levels. The remaining six blast crisis samples exhibited low levels of the aberrant transcript comparable to chronic phase cells. The two patients displaying the highest levels of the bcr-abl transcript did not harbor amplified copies of the bcr-abl fusion gene. This heterogeneity in the level of expression of the bcr-abl transcript in CML blast crisis indicates that enhanced expression of this aberrant transcript is not an absolutely necessary condition for blast transformation.

Adult↗

PubMed1983

[Analysis of specific cellular immunity in renal transplant recipients by MLR & CML].

The specific cellular immunity of renal transplant recipients was investigated by MLR & CML. MLR has been thought to reflect the disparity of HLA-D locus between two individuals and CML to represent an in vitro model for graft rejection and graft adaptation. Anti-donor and anti-control reactivities were diminished in MLR immediately after transplantation even during acute rejection. These MLR suppression are probably due to immuno-suppressive drugs. In acute rejection episode, CML reactivity against donor was elevated and well correlated with clinical findings, but on the other hand, MLR reactivity was suppressed. This discrepancy indicates that strong MLR is not needed to induce high CML. The in vitro development of cytotoxic T cells as a result of proliferation in MLR is impaired in long term survivors and quiescent recipients after transplantation. These suppression is directed to specific donor but not to unrelated third party cells. I have demonstrated the MHC restricted CML suppressor T cell by using HLA identical monozygous twin's lymphocyte. This suppressor T cell may prove to be of value in enhancing graft acceptance and play a part of immunomodulations.

Adult↗

PubMed1994

T lymphocytes in chronic myelogenous leukaemia (CML): no evidence of the BCR/ABL fusion gene detected by fluorescence in situ hybridization in 14 patients.

Previous studies designed to identify the Ph chromosome in T lymphocytes from patients with chronic myelogenous leukaemia (CML) were mostly based on small numbers of patients. To examine the possibility that the occasional CML patient might have major penetration of the T-cell compartment by the leukaemic clone, we studied interphase T cells from the blood of 11 CML patients conventionally treated in chronic phase and three in relapse after allogeneic bone marrow transplant (BMT) by fluorescence in situ hybridization using BCR and ABL cosmid probes. Granulocytes from the same patient and cells from the SD-1 CML cell line served as positive controls. Cells with juxtaposition of BCR and ABL signals or with the two signals up to one signal diameter apart were scored as positive. In each CML patient the incidence of 'positive' T cells was much less than in positive controls and similar to that found in negative controls (mean values +/- 1 SD: 7.7 +/- 3.6; 91.2 +/- 3.1, and 5.6 +/- 2.2, respectively). We conclude that none of the patients studied by this technique had any appreciable proportion of BCR/ABL-positive T cells in the circulation.

Adult↗

PubMed1993

[Chronic myeloid leukemia without Philadelphia chromosome (Ph-negative CML)].

Ph-negative chronic myeloid leukemia [Ph(-)CML] is a heterogenous group of conditions characterized by similar cytogenetic pattern but variable changes at the molecular level. All cases with BCR gene rearrangement in this group have clinical and haematological course similar to Ph(+)CML. However, CML without rearrangements of ABL and BCR genes, called "atypical CML", forms a separate entity showing clinical and morphological features different from classical CML.

Humans↗

PubMed1993

Interferon gamma is effective for BM purging in a patient with CML.

We report a case of Ph-positive CML where the BM was incubated for 24 h with 10(3) IU/ml IFN gamma and then cultured in liquid media for 4 weeks. After 24 h incubation, there was no differential sensitivity of CML CFU-GM to IFN gamma compared with untreated BM. Subsequent long-term culture (LTC) of the IFN gamma treated CML BM, however, demonstrated a 75% inhibition of production of CFU-GM from the second week onwards. Using PCR, we were able to demonstrate two types of BCR-ABL transcript in the diagnostic BM. After 4 weeks of LTC, the J(bcr b3/ABL II) RNA transcript persisted in the untreated BM, whereas neither BCR/ABL RNA transcripts were detected in the culture established with IFN gamma-treated CML BM. This study has two points of interest with the demonstration of (1) a possible antileukaemic effect of IFN gamma on the progenitors generated in the LTC system, and (2) the use of highly sensitive PCR technology to evaluate the effectiveness of IFN gamma to purge CML BM of Ph-positive cells.

Bone Marrow↗

PubMed1995

5-Fluorouracil-resistant CD34+ cell population from peripheral blood of CML patients contains BCR-ABL-negative progenitor cells.

Despite the marked expansion of leukemic cells observed in the hematopoietic system of chronic myeloid leukemia (CML) patients, there is clinical and experimental evidence that normal nonclonal cells persist in the bone marrow (BM) and peripheral blood (PB) of patients in the early chronic phase. In this study, we attempt to select the benign progenitor-enriched population from the PB of CML patients. The CD34+ cells isolated from the PB of 12 CML patients in the chronic phase were treated with low doses (5 or 10 micrograms/mL) of 5-fluorouracil (5-FU). We expanded these cells for 7 days in liquid cytokine-mediated cultures. This expansion in the presence of interleukin-1 (IL-1) plus stem cell factor (SCF) plus IL-3 or leukemia inhibitory factor (LIF) plus SCF plus IL-3 seemed at least to preserve the initial clonogenic potential of CD34+ and 5-FU-resistant CD34+ cells. For the presence of BCR-ABL, mRNA from each of the 12 patients was studied by reverse-transcriptase-polymerase chain reaction (RT-PCR) on 10-15 pooled CFU-GM colonies plucked from methylcellulose cultures of starting and expanded populations. Although all PCR results were positive for colonies harvested before liquid culture, we were able to identify BCR-ABL-negative colonies from an expanded CD34+ population cultured in the presence of recombinant cytokines in 11 of 12 patients studied. 5-FU pretreatment of CML CD34+ cells markedly reduced their clonogenic potential and growth factor-mediated cell proliferation but favored higher frequency of BCR-ABL-free colonies. In conclusion, these data show that 5-FU-resistant CD34+ cells from the PB of CML patients contain normal progenitor cells, which can be selected and expanded in short-term cytokine-mediated cultures.

Antigens, CD34↗

PubMedDate not supplied

The onset of CML in blastic crisis: molecular features.

The lack of distinguishing characteristics between lymphoid blastic crisis (BC) of Philadelphia (Ph)+ chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) remains an exciting dilemma. Indeed, the genetic defect of approximately half of Ph+ ALL patients is identical to that identified in CML. Here we report the case of one patient admitted with immunological and molecular patterns indicative of Ph+ ALL. The patient was brought into complete remission by chemotherapy and was transplanted with an HLA identical sibling donor, but relapsed a few months later with immunological and molecular evidence of BC of CML, displaying myeloid markers and lacking lymphoid antigens and immunoglobulin heavy chain (IgH) rearrangement. This suggest a CML case with an initial BC without a previous chronic phase or supervening on a subclinical CML.

Adult↗

PubMed1998

MCP-1, not MIP-1alpha, is the endogenous chemokine that cooperates with TGF-beta to inhibit the cycling of primitive normal but not leukemic (CML) progenitors in long-term human marrow cultures.

The long-term culture (LTC) system has been useful for analyzing mechanisms by which stromal cells regulate the proliferative activity of primitive normal, but not chronic myeloid leukemia (CML), hematopoietic progenitor cells. In previous studies, we identified two endogenous inhibitors in this system. One is transforming growth factor-beta (TGF-beta), which is equally active on primitive normal and CML progenitors. The other we now show to be monocyte chemoattractant protein-1 (MCP-1). Thus, MCP-1, when added to LTC, blocked the activation of primitive normal progenitors but did not arrest the cycling of primitive CML progenitors. Moreover, the endogenous inhibitory activity of LTC stromal layers could be overcome by the addition of neutralizing antibodies to MCP-1, but not to macrophage inflammatory protein-1alpha (MIP-1alpha). However, neither of these antibodies antagonized the inhibitory activity of NAc-Ser-Asp-Lys-Pro (AcSDKP) on primitive normal but not CML progenitor cycling in this system. Moreover, none of six other -C-C- or -C-X-C- chemokines, previously shown to inhibit primitive normal human CFC proliferation in semisolid assays, were found to act as negative regulators when added to normal LTC. These results provide further support for the concept that primitive CML progenitor cell proliferation is deregulated when these cells are exposed to limiting concentrations of multiple inhibitors, only some of which have differential actions on normal and Ph+/BCR-ABL+ cells.

Bone Marrow↗

PubMed1998

Detection of the bcr/abl gene in bone marrow macrophages in CML and alterations during interferon therapy--a fluorescence in situ hybridization study on trephine biopsies.

A fluorescence in situ hybridization (FISH) study was performed on trephine biopsies of the bone marrow in chronic myelogenous leukaemia (CML) to evaluate the bcr/abl translocation in macrophages before and during interferon (IFN) therapy. Mature macrophages and osteoclasts were identified by the monoclonal antibody PG-M1, which recognizes a fixative-resistant epitope of the CD68 molecule. In contrast to a control group, in 145 of 479 (30 per cent) macrophages of the CML bone marrow, a positive fusion signal was found, together with corresponding translocation sites in the surrounding myeloid cells. In patients following IFN treatment for approximately 12 months and with haematological/cytogenetic remission by clinical standards, this number was reduced to 10 of 136 (9 per cent) macrophages. In addition, the few multinucleated osteoclasts of the untreated CML bone marrow displayed positive translocation spots. This finding supports the hypothesis that stromal macrophages and osteoclasts are of haematogenic stem cell origin. Moreover, clinical remission and reduction of bcr/abl-positive macrophages under IFN therapy lend support to the hypothesis that the presence of malignant stromal macrophages may contribute to the selective expansion of leukaemic precursors and the suppression of normal haematopoiesis in CML.

Antigens, CD↗

PubMed1985

C-abl and bcr are rearranged in a Ph1-negative CML patient.

Chromosomal analysis of a patient with chronic myelocytic leukemia (CML) revealed a translocation (9;12) (q34;q21) without a detectable Philadelphia chromosome (Ph1). Using molecular approaches we demonstrate (i) a rearrangement within the CML breakpoint cluster region (bcr) on chromosome 22, and (ii) a joint translocation of bcr and c-abl oncogene sequences to the derivative chromosome 12. These observations support the view that sequences residing on both chromosome 9 (c-abl) and 22 (bcr) are involved in the generation of CML and suggest that a subset of Ph1-negative patients may in fact belong to the clinical entity of Ph1-positive CML.

Adult↗

PubMed2004

Treatment of CML in pediatric patients: should imatinib mesylate (STI-571, Gleevec) or allogeneic hematopoietic cell transplant be front-line therapy?

BACKGROUND: Long-term survival of pediatric patients with chronic myelogenous leukemia (CML) receiving myeloablative hematopoietic stem cell transplantation from fully-matched related and unrelated donors has been reported between 60 and 75%, but is associated with significant morbidity. Imatinib mesylate (STI-571, Gleevec) and reduced intensity conditioning stem cell transplantation (RIC) are two promising new tools that offer potential for decreasing therapy associated morbidity for patients with CML. RESULTS: Large trials have shown significant responses in chronic phase patients treated with imatinib and reasonable but short-lived responses in advanced phase CML. Data from adult studies is beginning to define populations likely to progress or have prolonged responses to imatinib, and some adult treatment paradigms are moving toward reserving transplantation until patients are at risk of failure with imatinib. Early trials of RIC transplantation in CML show decreased transplant related morbidity with efficacy similar to conventional transplantation, but the approach has yet to be verified in phase III studies. Data in pediatric patients with imatinib and RIC transplantation is limited. CONCLUSIONS: Studies with imatinib are underway in pediatrics, but whether pediatric dosing schemes will lead to outcomes similar to adults is unknown. Because HLA-matched myeloablative transplantation offers a high rate of cure in the pediatric population, clinical studies assessing the role of imatinib mesylate and RIC transplantation should be planned carefully in order to avoid sub-optimal outcomes.

Antineoplastic Agents↗

PubMed1997

Identification of translocational breakpoints within the intron region before the last coding exon (exon 12) of the EVI1 gene in two cases of CML-BC with inv(3)(q21q26).

We have previously shown that the EVI1 gene at chromosome 3q26 is transcriptionally activated by chromosomal rearrangements in acute myelogenous leukemias (AMLs) with inv(3)(q21q26) or t(3;3)(q21;q26). The breakpoints in t(3;3) cases were 15 to 330 kb upstream of the EVI1 gene, while those in inv(3) cases were 150 to 200 kb downstream and outside of the EVI1 coding region. The EVI1 gene is also activated in chronic myelogenous leukemia-blastic crisis (CML-BC) with inv(3)(q21q26); however, the molecular mechanism of EVI1 activation in CML-BC is still unclear. In this paper, we have analyzed chromosomal rearrangements in two leukemia cell lines derived from CML-BC with inv(3)(q21q26) and have identified the breakpoints within the EVI1 coding area. The EVI1 gene spans over 100 kb with 12 exons (10 coding exons), and the chromosomal breakpoints are clustered in the intron region before the last coding exon (exon 12). The nucleotide sequence of EVI1 cDNA clones from MOLM-1 cells was truncated at exon 11, and a novel sequence of 681 nucleotides was added at the 3' end of the EVI1 transcripts. The novel sequence was derived from a readthrough intron sequence 3' to the coding exon 11 adjacent to the breakpoint. The breakpoints at 3q21 were within the breakpoint cluster area downstream of the ribophorin I gene, suggesting that the activation mechanism of the EVI1 gene in CMLs with inv(3) is the same as that in AMLs with inv(3). These results indicate that expression of a truncated EVI1 gene is an important factor in the progression of CML.

Amino Acid Sequence↗

PubMed1976

Augmentation of cell mediated lysis (CML) by THF.

The in-vitro model of cell mediated lysis (CML) was used to study whether a thymic hormone (THF) participates in the processes which lead to generation of effector cells. It was found that THF increases the capacity of effector cells from spleens of intact mice in the CML assay. This effect of THF on generation of effector cells was manifested when THF was present during the mixed lymphocyte culture. On the other hand, addition of THF to the effector (CML) phase did not elevate the lytic capacity of killer cells. Moreover, THF compensated the impaired lytic capacity of effector cells from adult thymectomized mice and raised it to the level of intact mice. The results are compatible with the hypothesis that THF acts on the generation of CML effector cells of both intact and adult thymectomized mice.

Animals↗

PubMed1991

Cytogenetics of chronic myelogenous leukemia (CML) correlated to the histopathology of bone marrow biopsies.

Cytogenetic findings were correlated to histopathological bone marrow findings evaluated simultaneously in 103 patients with chronic myelogenous leukemia (CML). CML was subtyped histologically according to the number of megakaryocytes and increase of fibers or blasts within the bone marrow. The Philadelphia chromosome (Ph 1) was found in 88.3% of all patients (91/103). Chromosome aberrations additional to the Ph 1-chromosome were noticed in 20 of 91 (22%) cases. The additional karyotype changes occurred significantly more frequently among patients with increase of fibers in the bone marrow compared with patients without increase of fibers or blasts (p less than 0.05). Karyotype changes associated with increase of fibers in Ph 1-positive cases of CML were trisomy 8 and 19, +Ph1, t (1; 11), and i (17q). Ph 1-positive CML patients with additional karyotype changes had a significantly shorter survival (p less than 0.04) than Ph 1-positive patients without additional chromosome aberrations. Our results suggest that histopathological examination of the bone marrow should be considered in the evaluation of cytogenetic markers in chronic myeloproliferative disorders.

Adult↗

PubMed2002

Successful treatment with imatinib mesylate of a CML patient in megakaryoblastic crisis with severe fibrosis.

The prognosis of patients with chronic myeloid leukemia in blastic crisis (CML-BC) remains extremely poor, and multiagent chemotherapy regimens commonly used to treat acute leukemia offer only short-term benefits. Therefore, the advent of the novel molecularly targeted anticancer agent imatinib mesylate is a breakthrough in CML therapy. We present a CML patient in megakaryoblastic crisis with severe myelofibrosis, who was treated with imatinib at a dosage of 400 mg/day and achieved complete remission together with a marked regression of myelofibrosis after 1 month. The effect of imatinib on the long-term prognosis remains unclear, although the agent is clearly a promising drug for treating CML-BC even in cases of myelofibrosis.

Adult↗

PubMed1996

FISH analysis for CML monitoring?

Conventional cytogenetics is considered the gold standard for evaluating CML during interferon (IFN) treatment. Drawbacks to this approach are the small number of metaphases available during IFN therapy and the impossibility of scoring interphase cells. We applied, besides cytogenetics, double-color FISH (dc-FISH) detection of BCR-ABL gene fusion to monitor 20 CML patients on IFN. dc-FISH easily detected 200 cells per specimen, while with cytogenetic examination a mean of 16.1 mitoses per sample were scored. Though the correlation of dc-FISH and cytogenetic data was good (r = 0.77, p < 0.001), the discrepancy between the two methods as regards the proportion of leukemic cells in the marrow was often important dc-FISH detected a relevant proportion of BCR-ABL+ cells in three patients classified as complete cytogenetic responders and showed that, after 9-12 months of IFN treatment, a significant reduction of BCR-ABL+ cells was present in all the 20 patients tested. This might suggest that all CML patients are potentially responsive to IFN. Though more data are required, we think that dc-FISH is more informative than cytogenetic analysis for CML monitoring. Notably because of the simplicity of the procedure, this method could be easily standardized among different laboratories, thus permitting cross-comparison in therapeutic trials.

Cytogenetics↗

PubMed1990

Flow cytometric studies on actin polymerization in PMN cells from chronic myeloid leukemia (CML) patients.

Studies in our laboratory have shown that polymorphonuclear leucocytes (PMNL) from chronic myeloid leukemia (CML) patients are defective in chemotaxis towards a synthetic peptide, n-formyl-methionyl-leucyl-phenylalanine (FMLP), during the active phases of the disease and in remission. Actin plays a major role in cellular movements and binding of chemo-attractant to cells induces polymerization of G-actin to F-actin. We have, therefore, compared polymerization of actin in FMLP stimulated PMNL from CML patients with those from normal subjects by fluorescence microscopy and flow cytometry, using F-actin specific probe, NBD-phallacidin. Our results show that binding of FMLP to normal PMNL induces rapid conversion of G-actin to F-actin followed by depolymerization to some extent. In CML PMNL, such a biphasic response is not seen. Conversion of G-actin to F-actin is slower and F-actin content is significantly lower than that in normal PMNL. Moreover, organization of F-actin is different in CML PMNL as compared to that in normal PMNL.

Actins↗