Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of CML marrow in long-term culture (LTC) conditions may result in selection of normal (Ph-) LTC-initiating cells (LTC-IC) as early as 10 days, and in production of Ph- clonogenic cells and mature end cells within 5 weeks. This was the rationale for using marrow cells from 10-day-old LTC to autograft nine chronic phase CML patients, ineligible for HLA-matched sibling donor transplant, and who were selected on the basis of a pre-transplant screening LTC test. Of the transplanted patients three died; two of graft failure and one of therapy-related toxicity with 97% Ph- cells 16 months following the autograft. The reconstituting haemopoietic cells in the seven engrafted patients were 100% Ph- in four, > or = 90% Ph- in two and 71% Ph- in the seventh, with a duration of complete cytogenetic response of 6-12 months. Three patients reverted to chronic phase and 100% Ph+ haemopoiesis 27-36 months post-autograft. The other three patients remain in continuous haematological remission with 22% Ph- cells in one and complete cytogenetic remission in the other two 3-4 years post-autograft. IFN therapy was generally introduced on the first evidence of recurrence of Ph+ cells or of cytogenetic deterioration. Further strategies to modulate immune surveillance in vivo may improve the outcome of cultured marrow autografts which give an initial and rather prolonged bias towards Ph- haemopoiesis.
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PMID:Autografting in Philadelphia (Ph)+ chronic myeloid leukaemia using cultured marrow: an update of a pilot study. 916 40

Thirty-two adults (median age 36 years) with leukemia (15 AML, eight CML, six ALL, three CLL) persisting or relapsing 1-40 months (median 4) after allogeneic BMT (20 matched siblings, eight unrelated, four family mismatch) underwent immunotherapy to elicit GVHD. This comprised one or more of: infusion of donor cells (n = 22), stopping cyclosporine (n = 14), and administration of interferon-alpha2b (n = 15) or interleukin-2 (n = 4). Eight acute leukemia patients received chemotherapy as well. The time from relapse to immunotherapy was 0-1344 days (median 4). Acute and/or chronic GVHD developed in 17 patients. Response was not evaluable in three patients due to early toxic death. There was no response in 10 patients, whereas 19 showed objective response. Nine patients died due to toxicity and 10 due to progressive disease. Thirteen patients are alive 4-58 months (median 14) after immunotherapy; 12 in remission (five AML, four chronic phase CML, one ALL, one accelerated phase CML, one CLL) and one with progressive disease (accelerated phase CML). Eleven of 13 patients who are alive had GVHD compared with six of 19 who died (P = 0.005, Fisher's exact test). We conclude that with the exception of CML in myeloid blast crisis, immunotherapy is active in most types of acute and chronic leukemia relapsing after allogeneic BMT. It is associated with considerable toxicity. Clinically obvious GVHD, especially chronic GVHD, results in a higher probability of survival.
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PMID:Induction of graft-versus-host disease as immunotherapy of leukemia relapsing after allogeneic transplantation: single-center experience of 32 adult patients. 924 16

Chronic myeloid leukaemia (CML) can be treated successfully with allogeneic bone marrow transplantation (BMT) leading to long-term disease-free survival. Leukemia relapse, however, remains a significant clinical problem. Relapse following BMT presumably results from the expansion of small numbers of recipient leukaemic cells which have survived the conditioning therapy. In order to define patients who are at a high risk of leukaemia relapse, a variety of techniques have been employed to detect persistence of host haemopoiesis (mixed chimaerism, MC) or residual leukaemia (minimal residual disease, MRD). However, the precise relationship between the detection of MC and MRD post-BMT is unknown. We have investigated chimaerism and MRD status in 22 patients who were in clinical and haematological remission post-allogeneic BMT for chronic phase CML. Chimaerism was assessed using short tandem repeat PCR (STR-PCR) while BCR-ABL mRNA detection using reverse transcriptase polymerase chain reaction (RT-PCR) was performed to detect the presence of MRD. Seventeen patients received unmanipulated marrow (non-TCD) while in five patients a T cell-depleted transplant (TCD) was performed as additional GVHD prophylaxis. Chimaerism was evaluated in 18 patients (14 non-TCD, four TCD). Mixed chimaerism was an uncommon finding in recipients of unmanipulated BMT (21%) when compared to TCD BMT (100%). No evidence of MRD, as identified using the BCR-ABL mRNA RT-PCR assay, was detected in those patients who were donor chimaeras. Early and transient MC and MRD was detected in four patients (two non-TCD, two TCD) who have subsequently converted to a donor profile. One patient has stable low-level MC but remains MRD negative 4 years post-BMT. Late MC and MRD was observed in two patients who relapsed >6 years after TCD BMT for CML. We conclude that mixed chimaerism is a rare event in recipients of unmanipulated BMT and that donor chimaerism as detected by STR-PCR assay is consistent with disease-free survival and identifies patients with a low risk of leukaemic relapse post-BMT for CML.
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PMID:Persistent donor chimaerism is consistent with disease-free survival following BMT for chronic myeloid leukaemia. 925 92

The 9;22 chromosomal translocation characteristic of CML results in a fused bcr/abl gene and an abnormal fusion protein, p210bcr/abl. Relative to normal c-abl, p210bc1/abl has elevated tyrosine kinase activity that is essential for its transforming activity. We recently reported a prominent 62 kDa GAP-associated P-tyr protein and five additional consistent but less prominent P-tyr proteins as well as five more minor P-tyr proteins that are constitutively tyrosine phosphorylated in primary primitive lineage negative (lin-) chronic phase CML blasts but not in comparable primary lin- normal blasts. The GAP-associated p62 protein has now been purified, sequenced and its gene has been cloned; it is a previously unidentified protein and is currently being characterized. In analyzing P-tyr proteins in primary lin- normal blasts in response to various hematopoietic cytokines, we found a striking similarity in the tyrosine phosphorylation of four major and three minor proteins after stimulation with c-kit ligand (KL) and the P-tyr proteins that are constitutively phosphorylated in primary primitive lin- chronic phase CML blasts. Other cytokines tested (ie GM-CSF, G-CSF, IL-3, FLT3 ligand, TPO, EPO) were much less active or stimulated phosphorylation of other proteins. KL/c-kit and bcr/abl have some similar activities including enhancing survival and expansion of hematopoietic progenitor cells, probably acting primarily on early progenitors at the time of lineage commitment rather than on self-renewing stem cells. Activation of growth factor receptors promote a cascade of protein phosphorylations that can ultimately result in a wide range of cellular responses. Sustained activation of discrete signaling pathways in some types of cells results in differentiation, whereas transient activation instead causes a proliferative response; in other cell types, the converse is true. It may be postulated that stem cells and primitive progenitors are at a particularly susceptible stage of development that renders them especially responsive to sustained bcr/abl-induced phorphorylation of a number of signaling proteins that are components of critical regulatory pathways, including c-kit. The affected pathways control and coordinate multiple diverse cell processes including proliferation, differentiation, maturation and apoptosis, processes that are normally tightly regulated and integrated. Perturbation of these key pathways in primitive progenitors would be expected to seriously disrupt orderly hematopoiesis and could also explain the multiple subtle pleiotropic biological abnormalities characteristically observed in later maturing CML compartments that we have collectively designated 'discordant maturation'. The true situation is undoubtedly very complex and involves interaction of multiple cytokines and signaling pathways that we are now trying to define. Constitutive downstream activation of critical pathways in susceptible early progenitors that normally require KL or other factors for activation could explain most if not all features of the disease.
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PMID:New understanding of the pathogenesis of CML: a prototype of early neoplasia. 952 44

Philadelphia chromosome-positive (Ph+) hemopoietic cells predominate in patients with chronic myeloid leukemia (CML) in chronic phase, but some Ph presumably normal stem cells persist in most patients. Ph cells are relatively frequent, compared to mature cell populations, in primitive hemopoietic cell populations from CML patients. We have purified CD34+ cells from chronic phase CML blood and separated them into two fractions on the basis of adherence or non-adherence to tissue culture plastic. We also separated CD34+ CML cell populations into HLA-DR(hi) and HLA-DR(lo) fractions and CD38(hi) and CD38(lo) fractions by flow cytometry. The CD34+ cells that adhered to plastic were predominantly CD33-, CD38- and HLA(-)-DR; cells with these phenotypic properties were significantly rarer in the CD34+ non-adherent cell population (P = 0.008-0.02). Expression of p210 BCR/ABL mRNA by adherent, non-adherent, HLA-DR(hi) and HLA-DR(lo)CD34+ cell subpopulations was demonstrated by RT-PCR. Using fluorescence in situ hybridization (FISH) in conjunction with BCR and ABL probes we detected Ph+ and Ph- cells in both adherent and non-adherent CD34+ cell fractions of 15/15 patients studied and in the HLA-DR(lo) or CD38(lo) sorted CD34+ cell fractions. The concentration of Ph- cells in the adherent CD34+ cell fraction was three-fold higher than in the non-adherent fraction (P = 0.001). Ph- adherent cells were detected in untreated CML patients and as late as 6 years after diagnosis of CML in patients treated with hydroxyurea (HU) or interferon-alpha (IFN-alpha). We conclude that whilst appreciable numbers of Ph- primitive hemopoietic progenitors are present in the circulation in untreated patients and also in treated patients in late chronic phase, the majority of cells expressing CD34 but not CD33, CD38 or HLA-DR antigens, are part of the CML clone.
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PMID:BCR/ABL-negative progenitors are enriched in the adherent fraction of CD34+ cells circulating in the blood of chronic phase chronic myeloid leukemia patients. 930 2

The aim of this study was to investigate the influence of interferon-alpha (IFN-alpha) on bone marrow fibrosis associated with chronic myelogenous leukemia (CML). Eighty-two bone marrow biopsies from 41 patients in chronic phase CML were stained with Snook's reticulin stain for argyrophilic fibers. Grading of reticulin fibrosis (scale of 1 to 4) was according to the quantity and pattern of distribution of reticulin. The interval between biopsies was a median of 25 months (range 12 to 40 months). Patients had been treated with IFN-alpha for at least 12 months, were still on IFN-alpha therapy during the study, and had achieved at least a complete hematological response. Before the start of IFN-alpha therapy, reticulin fibrosis was grade 1-2 in 23 patients (56%) and grade 3-4 in 18 (44%). During IFN-alpha therapy, reticulin fibrosis in bone marrow did not worsen or was reduced in 33 patients (80%) and increased by one grade in eight patients (20%). Only five patients (12%) with limited fibrosis (grade 1-2) before start of IFN-alpha therapy showed an increase towards significant fibrosis (grade 3-4), while eight of the 18 patients (44%) with grade 3-4 fibrosis achieved a decrease of fiber content in bone marrow. In summary, IFN-alpha was not associated with an enhancing effect on myelofibrosis in patients with CML and may have prevented increasing fibrosis in patients who respond to therapy.
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PMID:Effect of interferon-alpha therapy on bone marrow fibrosis in chronic myelogenous leukemia. 943 22

Twenty-seven patients above 40 years of age (range 40-55) with leukaemia underwent transplantation with haematopoietic stem cells from HLA-A, -B and -DR identical unrelated donors. They were compared to 69 younger patients, median age 23. In the older group, the diagnoses were acute myeloid leukaemia (AML) five, acute lymphoblastic leukaemia (ALL) three and chronic myeloid leukaemia (CML) 19. The corresponding figures in the younger patients were 21, 27 and 21, respectively. Conditioning consisted of cyclophosphamide (120 mg/kg) combined with 10 Gy total body irradiation. Immunosuppression was ATG or OKT3 for 5 days before transplantation and methotrexate combined with cyclosporin A. The probabilities of grades II-IV acute graft-versus-host disease (GVHD) were 23 and 21%, and the cumulative incidences of chronic GVHD were 64 and 50% in the older and younger patient cohorts, respectively. Overall, 3-year transplant-related mortality rates were 46% in patients > or =40 years of age and 32% in patients <40 years of age (P = 0.16). Three-year patient survival rates were 54 and 46% in the two groups, respectively. In patients with chronic phase CML, the corresponding figures were 67 and 68%, respectively. We conclude that patients above 40 years of age should be considered for transplantation with marrow from unrelated donors.
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PMID:Transplantation with unrelated bone marrow in leukaemic patients above 40 years of age. 948 93

We have previously shown that intravenously injected peripheral blood (PB) or bone marrow (BM) cells from newly diagnosed chronic myeloid leukemia (CML) patients can engraft the BM of sublethally irradiated severe combined immunodeficient (SCID) mice. We now report engraftment results for chronic phase CML cells in nonobese diabetic (NOD)/SCID recipients which show the superiority of this latter model. Transplantation of NOD/SCID mice with 7 to 10 x 10(7) patient PB or BM cells resulted in the continuing presence of human cells in the BM of the mice for up to 7 months, and primitive human CD34+ cells, including those detectable as colony-forming cells (CFC), as long-term culture-initiating cells, or by their coexpression of Thy-1, were found in a higher proportion of the NOD/SCID recipients analyzed, and at higher levels than were seen previously in SCID recipients. The human CFC and total human cells present in the BM of the NOD/SCID mice transplanted with CML cells also contained higher proportions of leukemic cells than were obtained in the SCID model, and NOD/SCID mice could be repopulated with transplants of enriched CD34+ cells from patients with CML. These results suggest that the NOD/SCID mouse may allow greater engraftment and amplification of both normal and leukemic (Ph+) cells sufficient for the quantitation and characterization of the normal and leukemic stem cells present in patients with CML. In addition, this model should make practical the investigation of mechanisms underlying progression of the disease and the development of more effective in vivo therapies.
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PMID:High level engraftment of NOD/SCID mice by primitive normal and leukemic hematopoietic cells from patients with chronic myeloid leukemia in chronic phase. 951 40

CML, characterized by the BCR/ABL gene rearrangement has been more extensively studied than any other malignancy. Over the last decade, significant progress has been made in our understanding of BCR-ABL-induced alterations in intracellular signaling. Unfortunately, we still only poorly understand the correlation between the clinical symptoms of chronic phase CML and the BCR-ABL oncoprotein. This is in part due to lack of a good in vivo animal model of chronic phase CML. In vivo and in vitro studies from the Clarkson group, recently reviewed in this journal (Leukemia 1997; 11: 1404-1428), have significantly enhanced our understanding of the pathophysiology of CML. However, further characterization of the effect of the BCR-ABL oncoprotein on signal molecules involved with cell differentiation, cell proliferation, cell survival and cell adhesion in primary Ph+ CML progenitors or in vivo models of CML will be needed to provide a full understanding of the pathophysiology of chronic phase CML.
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PMID:Chronic myelogenous leukemia: too much or too little growth, or both? 930 92

This article reviews the biology of chronic myelogenous leukemia (CML) and its effect on the process of hematopoiesis. The relevance of the BCR-ABL fusion protein as well as murine models are also discussed. CML has been studied more extensively than any other malignancy, yet the correlation between the clinical symptoms of chronic phase CML and the BCR-ABL oncoprotein is poorly understood. Insights from recent efforts both to develop a good in vivo animal model and to characterize the effect of the BCR-ABL oncoprotein on relevant signal molecules may lead to a better understanding of the pathophysiology of chronic phase CML and, thereby, to the development of targeted therapeutic approaches.
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PMID:Biology of chronic myelogenous leukemia. 952 24


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