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PubMed2005

The incidence and patterns of BCR/ABL rearrangements in chronic myeloid leukaemia (CML) using fluorescence in situ hybridisation (FISH).

INTRODUCTION: Chronic myeloid leukaemia (CML) is characterised by the formation of the BCR/ABL fusion gene, usually as a result of the Philadelphia (Ph) translocation between chromosomes 9 and 22. MATERIALS AND METHODS: The incidence of both typical and atypical BCR/ ABL gene rearrangements was determined in 110 patients suspected of CML using dual fusion fluorescence in situ hybridisation (DF-FISH) probes. RESULTS: Eighty-seven per cent of CML patients showed Ph translocation while 13% were negative for the Ph chromosome. About 71.9% of Ph-positive patients displayed the typical DF-FISH signal pattern. Atypical patterns among the Ph-positive patients included the concurrent loss of residual proximal 9q and distal 22q (10.4%), complex translocation with additional partners (9.4%), supernumerary Ph (3.1%), loss of residual 9q sequences proximal to breakpoint (3.1%), and deletion of distal derivative 22q signal (2.1%). Cryptic genetic alterations with loss of proximal 9q sequences were found in 13.5% of CML Ph-positive patients, which is associated with poor prognosis. Fusion signals were detected in 57.1% of CML Ph-negative patients, indicating cryptic BCR/ABL rearrangements (i.e., masked Ph). CONCLUSION: FISH is able to detect BCR/ABL fusion in CML with masked or variant Ph not apparent with conventional karyotyping. Establishment of signal patterns with FISH is important as atypical patterns may have clinical prognostic implications.

Gene Rearrangement↗

PubMed1991

[Rearrangement and expression of bcr-abl genes in CML and ALL].

We have carried out the molecular and cell-biological analysis on Ph1-positive leukemias in this study. Five out of nine Ph1-positive ALL cases showed molecular rearrangement within the classical bcr sequence (or M-bcr), similar as those in 47 CML cases. We examined 4 cases of Ph1-positive ALL presenting no rearrangement of M-bcr and found that, in 2 of 4 cases, one showed the breakpoint in a 5 kb segment of the bcr gene first intron (bcr-2) and the other in bcr-1, 16 kb upstream of bcr-2. Ph1-positive ALL frequently showed biphenotypical or biclonal phenotypes of myeloid and lymphoid lineages. Furthermore, we demonstrated the ability of two Ph1-positive ALL cell lines to differentiate into monocytic lineage in vitro, thus suggesting the possibility that these Ph1-positive ALL cells might reside on the stage of multipotent stem cell along the hematopoietic cell differentiation. Two out of 31 CML cases showed the mutations of the ras genes by the polymerase chain reaction; one case in the crisis phase and the other in the chronic phase. However, no mutations of the fms genes was detected. Two cases in the crisis phase of 24 CML patients (11 cases in the chronic phase and 13 cases in the crisis phase) contained rearrangements of the p53 gene by Southern analysis. Furthermore, the transcriptional alteration was found in 2 CML-BC and 2 CML-BC derived cell lines' samples, suggesting a important role of the p53 gene in the transformation of CML into the crisis phase.

Chromosome Fragility↗

PubMed1978

Cytogenetic "staging" of chronic myeloid leukemia (CML).

Establishment of the exact chromosome constitution in the leukemic cells of CML can serve as a mean of "staging" of the disease. Such "staging" is of more than theoretical value, for it may be utilized not only in the differentiation of the type of CML present, but may also serve as a useful guide in the therapy of the disease. The most important determination is to ascertain whether the CML is Ph1 positive or negative, for the latter form of the disease has a much poorer prognosis and requires a different therapeutic approach than the Ph1-positive disease. A system of "staging" of Ph1-positive CML is proposed, allowing a clear understanding of the type of therapy to be used and the results that can be expected from such therapy. The presence or absence of chromosomally normal cells plays a crucial role in this respect and points to the importance of diagnosing CML in its very early stages, when normal cells are usually present and leading to a much more favourable prognosis. The possible role of a missing Y in the leukemic cells and Ph1-translocations other than the standard one in the prognosis and clinical picture of CML is discussed.

Chromosome Aberrations↗

PubMed1980

Growth pattern and SCE incidence in Ph1-positive cells of CML.

The incidence of sister chromatid exchange (SCE) and growth pattern were studied in vitro with a bromodeoxyuridine (BrdU) chromosome labelling technique in the Ph1-positive leukaemic marrow and/or blood cells from 20 patients with chronic myelocytic leukaemia (CML) at various stages of the disease. Additional chromosome abnormalities, besides the Ph1 or unusual Ph2-translocations, were found in three out of twelve cases in the chronic phase (CP), in two of four cases entering the blastic phase (BP), and in all four cases in the BP during the study. The growth pattern and SCE incidence in these cases were similar to those in cases in the BP during the study. The growth pattern and SCE incidence in these cases were similar to those in cases with a Ph1 as the sole abnormality. Ph1-positive CML cells undergoing second or more generations predominated in the marrow in the CP, whereas in the active stage of the CP and in the BP the CML marrow cells tended to go through only one generation. There were no clear correlations between the SCE incidence and the state of the CML. However, a marked increase in the SCE frequency was observed in some cases after chemotherapy, irrespective of the state of the disease. The results indicate that the type of Ph1-translocation and/or the presence of additional karyotypic abnormalities hardly affect the growth pattern and SCE incidence in the Ph1-positive CML cells, and that the in vitro BrdU-labelling methods may have a potential for detecting chemotherapeutic effects in CML patients and in the 'staging' of the clinical course of such patients.

Blood Cells↗

PubMed1995

Enhanced elimination of Ph+ chromosome cells in vitro by combined hyperthermia and other drugs (AZT, IFN-alpha, TNF, and quercetin): its application to autologous bone marrow transplantation for CML.

Autologous bone marrow transplantation (ABMT) for chronic myelogenous leukemia (CML) is limited because of the difficulty in purging Ph chromosome positive cells from bone marrow cells (or peripheral blood stem cells). Combining hyperthermia with certain drugs that affect Ph+ cell growth in vivo and in vitro may enhance the killing (apoptosis) of CML cells in vitro. In this study, we chose such drugs (i.e., azidothymidine [AZT], interferon-alpha [IFN-alpha], tumor necrosis factor [TNF], and quercetin) and tested this hypothesis using two CML-derived cell lines in vitro, K562 and KU812, to enhance the killing of CML cells with heat. Our results indicate that the optimal hyperthermic purging effect is achieved by heating at 42 degrees C for 1 hour with IFN-alpha (100 U/mL) and AZT (0.5 microM/L) or with quercetin (50 microM) [corrected], depending on the sensitivity of the CML cells eliminated in vitro. K562 cells were significantly eradicated by a combination of IFN-alpha and AZT, while KU812 cells were significantly inhibited by quercetin at the temperature and drug concentrations above. This combined effect may enhance apoptosis of CML cells in vitro.

Apoptosis↗

PubMed1994

Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group.

As curative bone marrow transplantation is available only to a minority of patients with chronic myelogenous leukemia (CML), drug therapy remains of central interest. Several nonrandomized studies have suggested that interferon-alpha (IFN) may prolong survival in CML. In a randomized multicenter study the influence of IFN versus busulfan or hydroxyurea (HU) on survival of Philadelphia-positive (Ph+) CML was examined. A total of 513 Ph+ patients were randomized for treatment as follows: 133 for IFN, 186 for busulfan, and 194 for HU. IFN-treated CML patients have a significant survival advantage over busulfan-treated (P = .008), but not over HU-treated patients (P = .44). The longer survival is due to slower progression to blast crisis. Median survival of IFN-treated patients is 5.5 years [5-year survival, 59%; 95% confidence interval (CI), 48%-70%], of busulfan-treated patients, 3.8 years (5-year survival, 32%; CI, 24%-40%), and of HU-treated patients, 4.7 years (5-year survival, 44%; CI, 36%-53%). Patients who continue on IFN survive longer than those in whom IFN is discontinued before blast crisis (P = .007). Complete hematologic IFN-responders have a survival advantage over partial responders or nonresponders (P = .02). Cytogenetic IFN-responders have no significant survival advantage over nonresponders (P = .2). Patients who attain white blood cell (WBC) counts of 10 x 10(9)/L or less have a survival advantage in the IFN (P = .007) and HU (P = .05) groups. Whereas toxicity in the IFN group was considerably higher than in the busulfan or HU groups, long-lasting cytopenias necessitating discontinuation of therapy as observed with busulfan have not been seen with IFN or HU. The problems of conventional prognostic scores (Sokal's score, Score 1) that we observed in IFN-treated patients support the idea that IFN changes the natural course of CML. We conclude that, with regard to survival of CML in the chronic phase, IFN is superior to busulfan and as effective as HU. Whether and to what extent IFN is superior to HU appears to depend, at least in part, on the degree of WBC suppression by HU-therapy and on the risk profile of the patients.

Adolescent↗

PubMed1993

In vitro culture of bone marrow cells for autografting in CML.

Long-term maintenance of normal hematopoiesis in vitro is possible when very primitive progenitors are cocultivated with certain non-hematopoietic stromal cells that may co-exist in (or be derived from cells that co-exist in) hematopoietic tissues. Such long-term cultures (LTC) have been used to develop quantitative assays for the most primitive populations of hematopoietic cells currently detectable in adult marrow. In addition they provide a unique model for analysis of the complex molecular mechanisms that may regulate primitive hematopoietic cell population dynamics in vivo. Similar studies with LTC of cells from patients with chronic myeloid leukemia (CML) have made it possible to detect and characterize very primitive neoplastic cell populations in this disease. These latter studies have revealed differences in the properties of primitive CML cells that both reflect and explain their increased turnover and are thus presumably part of the mechanism that enables the neoplastic clone to expand in vivo. In addition, the most primitive neoplastic cells in CML patients are abnormally distributed between the marrow and blood and their ability to maintain their numbers in LTC has also been found to be defective. Assessment of the number and behaviour of primitive cells in LTC of CML marrow has been used to identify those patients most likely to benefit from intensive therapy supported by transplantation of cultured autologous marrow. Twenty-two such CML patients have now been treated with this experimental protocol. The results to date have clearly established the feasibility of this novel treatment strategy and, together with more recent laboratory findings, suggest future avenues for significantly improving the management of CML patients.

Bone Marrow Transplantation↗

PubMed1984

Investigations on karyotype evolution in patients with chronic myeloid leukemia (CML).

In an attempt to relate karyotype evolution to clinical and hematological data serial chromosomal analyses were performed in 31 patients with chronic myeloid leukemia (CML), both in chronic and acute phases. Our results in Philadelphia chromosome (Ph1)-positive CML are in line with karyotype profiles described in the literature. In addition, we report on chromosomal findings in 4 cases of Ph1-negative disease, one presenting with an iso17q chromosome in the positive CML. The same chromosomal abnormality was observed in a small population of Ph1-negative cells present in one of two patients with mixed Ph1-positive/Ph1-negative CML. The first case of a female patient with the loss of a sex chromosome in Ph1-positive cells is reported. Two patients with unusually long and mild chronic phases despite the presence of trisomy 8 in their karyotypes are described. Our findings suggest that the order of appearance of additional chromosomal changes of CML is of prognostic significance for the progression and the clinical picture of the disease.

Adult↗

PubMed1988

Randomized study on the treatment of chronic myeloid leukemia (CML) in chronic phase with busulfan versus hydroxyurea versus interferon-alpha.

For palliative therapy during the chronic phase of CML busulfan has proved to be the drug of choice. During the past years hydroxyurea and also interferon-alpha have gained increasing significance since they might prolong the duration of the chronic phase. In a multicenter study it is being determined, whether the use of hydroxyurea or of interferon-alpha instead of busulfan prolongs the duration of the chronic phase of Philadelphia positive CML. Additional goals are the examination of whether the types of disease evolution and the terminal phases differ between the treatment groups, and the prospective recognition of prognostic criteria for the duration of the chronic phase of CML. By December 31, 1987, 326 CML-patients had been randomized, 150 for busulfan, 150 for hydroxyurea and 26 for interferon-alpha. The average age is 50 years. 59 patients reached the end of the chronic phase, 55 died. The mean observation time of all patients is 1.34 years. At present no significant difference in survival is recognizable between the busulfan and hydroxyurea groups. Fewer adverse effects have been observed in the hydroxyurea group. Philadelphia chromosome negative patients show a higher average age and tend to have lower white blood cell and platelet counts. The number of patients having received interferon-alpha is still too small to allow evaluation. This report intends to document organization and progress of this study which to our knowledge is, at present, the largest ongoing prospective multicenter study on the therapy of CML.

Busulfan↗

PubMed2006

Targeting of gene expression by siRNA in CML primary cells.

Development of array methods contributes to elucidation of many genes expressed during oncogenesis. Our array-based analyses of gene expression in patients with chronic myeloid leukemia (CML) revealed several genes (MMP8, MMP9, PCNA, JNK2, MAPK p38) with significant increased expression. We suppose that the genes may be implicated in the disease development and a siRNA-suppression can elucidate their functions in leukemogenesis. One of the crucial requirements for this purpose is a high efficiency of siRNA delivery into CML primary cells. Using fluorescein-labeled siRNAs we systematically tested a variety of physical and chemical non-vector based transfection methods in order to evaluate which of them gave the most suitable transfer. Chemically synthesized siRNAs against mentioned genes were transfected into the cells and level of knockdown was determined by real time RT-PCR. Chemical transfection reagents (Oligofectamine, Metafectene, siPORT Amine) commonly used to transfect siRNAs in CML cell lines showed very low siRNA delivery in CML primary cells-mRNA levels decreased at the most to 76%. Electroporation achieved better results (suppression to 63%) but it was associated with high degree of cell death (more than 60%). In the study we obtained the best transfection efficiency using nucleofector technology. Gene expressions ranged 22-37% that remained from original levels. According to our results, nucleofection appears to be the only suitable non-viral method for siRNA delivery into the hard-to-transfect CML primary cells.

Adult↗

PubMed1985

Defective chemotaxis and adherence in granulocytes from chronic myeloid leukemia (CML) patients.

Adherence and motility of granulocytes from chronic myeloid leukemia (CML) patients was compared with that of granulocytes from normal subjects. The percentage of non-adherent granulocytes was significantly higher in untreated CML patients and patients in relapse and acute blastic crisis (ABC) (P less than 0.01). Chemotactic Index (C.I.) of granulocytes moving in a gradient of a synthetic chemoattractant F-Met-Leu-Phe was measured by time-lapse cinématography. While 84.5 +/- 3.53% of normal granulocytes were motile, only 30.3 +/- 14.7% granulocytes from untreated patients, 33.8 +/- 21.3% granulocytes from relapse patients and 36 +/- 9.9% granulocytes from ABC patients were found to be motile. The C.I. of motile granulocytes from CML patients was significantly lower in untreated patients (P less than 0.05), in patients in relapse (P less than 0.01) and in patients in ABC (P less than 0.05), as compared to that of normal granulocytes. Visualization of cytoplasmic actin by indirect immunofluorescence, revealed the presence of actin in granulocytes from patients in all stages of the disease. Thus, granulocytes from CML patients were defective in directional locomotion. Organized actin filaments were found in the small percentage of motile cells still found in CML patients.

Actins↗

PubMed1982

Variant Ph1 translocations in CML and their incidence, including two cases with sequential lymphoid and myeloid crises.

A serial cytogenetic study of 110 cases of chronic myelogenous leukemia (CML) has been performed with G- and/or Q-banding techniques with the following results. (1) Seven out of the 110 cases were karyotypically normal. (2) A variant Ph1 translocation was observed in three cases. In one case, the leukemic cells contained two reciprocal translocations, i.e., a t(3;9) (q21;q34) and a t(17;22)(q21;q11); therefore, a Ph1 chromosome was masked by a translocation of the deleted material from the 17q onto the band q11 of the long arm of a chromosome No. 22. In the second case, a variant Ph1 translocation involved chromosomes No. 9, 20, and 22, resulting in a karyotype interpreted as 46,XX,t(9q+;20q+;22q-); in this rearrangement, one of the segments, i.e., 9q31 or 9q33, seemed to be interstitially deleted and inserted into the interstitial region (q11) of a chromosome No. 20 and the 22q11 leads to qter was translocated onto the 9q. This is the first case in which chromosome No. 20 was involved in a variant Ph1 translocation. In the third case, the karyotype of leukemic cells was interpreted as 46,XX,t(5;9;22)(q13;q34;q11). (3) The frequency of Ph1-negative CML and that of Ph1-positive CML with various types of Ph1 translocation from 15 studies reported as series of 25 or more cases, including the present study, have been tabulated. The incidence of a variant Ph1 translocation was 4.1% (42/1027 cases of Ph1-positive CML); of the 42, 13 were of a simple type and 29 of a complex type. (4) In one case of the present study, a masked Ph1 by a translocation of material onto the short arm of the 22q- was observed in the blastic crisis but not in the chronic phase. From the present study and a review of the published cases, it appears that the incidence of such a "masked" Ph1, which cannot be detected by conventional Giemsa staining, is less than 0.6% in CML cases. (5) The first and the second cases with a variant Ph1 translocation mentioned above developed a myeloid blastic crisis after the induction of remission of a lymphoid blastic crisis. For the present, it is unclear whether the occurrence of such blast cells in the two cases and the cytogenetic findings are coincidental. However, the evidence supports the notion of "lymphoid-myeloid" multipotentiality of certain leukemic cells.

Adult↗

PubMed1985

The significance of cytogenetic findings of erythroid colonies derived from a Ph+ ALL patient: fundamental differences between Ph+ ALL and blastic phase CML.

Cytogenetic analysis was performed on colonies from erythroid burst-forming units (BFU-E) derived from bone marrow (BM) cells of a Ph-positive acute lymphocytic leukemia (Ph+ ALL) patient. A normal diploid karyotype was revealed in all 15 metaphases that could be analyzed in the erythroid colonies. Previous cytogenetic analyses of erythroid colonies obtained from BM cells of patients with Ph+ chronic myelogenous leukemia (CML) revealed that Ph-positive karyotypes were predominant in all 11 cases. Two of them were also examined in blastic phase (BP) and showed 100% Ph+ cells in BFU-E-derived colonies. The present findings suggest that the leukemic process of Ph+ ALL does not involve the erythroid series, which is in contrast to the involvement in CML. This is considered to be a fundamental difference between Ph+ ALL and the blastic phase of CML (BP CML). Clinically, cytogenetic analysis of erythroid colonies from BM cells may constitute a valuable approach for the differential diagnosis between Ph+ ALL and the BP of Ph+ CML.

Bone Marrow↗

PubMed1991

Pure red cell aplasia in a case of Ph negative BCR/ABL rearranged CML with t(12;14)(q23;p11).

A patient with chronic myelogenous leukemia (CML) associated with pure red cell aplasia (PRCA) is reported. The occurrence of PRCA has been described previously in sporadic cases of Philadelphia chromosome (Ph) positive CML. In this patient, however, the Ph-chromosome was not detected; cytogenetic analysis revealed a t(12;14)(q23;p11) as the sole abnormality. Molecular studies by Southern and PCR analyses showed the rearrangement of the BCR and ABL sequences and expression of the chimeric bcr/abl mRNA, thus confirming the diagnosis of CML. To our knowledge, this is the first report on a case of PRCA associated with Ph negative CML at diagnosis. The possible connection between CML and PRCA is discussed.

Aged↗

PubMed1999

ALL- and CML-type BCR/ABL mRNA transcripts in chronic myelogenous leukemia and related disorders.

Using the reverse transcription polymerase chain reaction, we investigated acute lymphoid leukemia (ALL)-type, and chronic myelogenous leukemia (CML)-type BCR/ABL mRNA expression in a total of 66 patients with chronic myeloproliferative disorder (CMPD). Thirty-six of 37 patients with CML were positive for CML-type mRNA. Thirteen of the 25 CML had ALL-type mRNA expression. The patients with ET, PV, MF, and CMML did not have any detectable BCR/ABL expression. The most remarkable finding was that two patients, a Ph1-positive CML patient and a patient with a presumptive diagnosis of essential thrombocythemia (ET), showed only ALL-type chimeric mRNA expression.

Adult↗

PubMed2006

[Tyrosine kinase inhibitors for the treatment of CML].

Chronic myelogenous leukemia is characterized by the Philadelphia-chromosome, a shortened chromosome 22 which is the result of a reciprocal translocation between chromosome 9 and 22. The fusion gene is called BCR-ABL. After transcription and translation the constitutively activated p210 BCR-ABL oncoprotein is formed. This leads to uncontrolled activation of the ABL tyrosin kinase. Deregulated cellular proliferation and diminished apoptosis of BCR-ABL transformed cells is the result. Expression of the BCR-ABL oncoprotein is sufficient and necessary for the development of a CML phenotype. Imatinib mesylate (Glivec) is a small molecule that binds to the ATP pocket of ABL and blocks downstream signalling events. Imatinib is very effective in the treatment of CML in all stages of the disease. Patients with newly diagnosed chronic phase CML were randomized to imatinib or to interferon plus cytarabine in the IRIS trial. Imatinib showed significantly superior tolerability, hematologic and cytogenetic resposes and increased time to progression. In patients with advanced phase CML, imatinib is less effective and response duration is short. Median overall survival of blast crisis patients is 6.9 months only. Additional BCR-ABL independent chromosomal abnormalities are common in advanced phase CML and result in resistance to imatinib. BCR-ABL kinase-domaine mutations are frequently found in imatinib resistant patients and confer diminished sensitivity to imatinib. Second generation, more powerful ABL kinase inhibitors, which are effective against most of the known mutations are currently tested in clinical trials.

Animals↗

PubMed2006

A novel triple purge strategy for eliminating chronic myelogenous leukemia (CML) cells from autografts.

Imatinib-refractory chronic myelogenous leukemia (CML) patients can experience long-term disease-free survival with myeloablative therapy and allogeneic hematopoietic cell transplantation; however, associated complications carry a significant risk of mortality. Transplantation of autologous hematopoietic cells has a reduced risk of complications, but residual tumor cells in the autograft may contribute to relapse. Development of methods for purging tumor cells that do not compromise the engraftment potential of the normal hematopoietic cells in the autograft has been a long-standing goal. Since primitive CML cells differentiate more rapidly in vitro than their normal counterparts and are also preferentially killed by mafosfamide and imatinib, we examined the purging effectiveness on CD34(+) CML cells using a strategy that combines a brief exposure to imatinib (0.5-1.0 microM for 72 h) and then mafosfamide (30-90 microg/ml for 30 min) followed by 2 weeks in culture with cytokines (100 ng/ml each of stem cell factor, granulocyte colony-stimulating factor and thrombopoietin). Treatment with 1.0 microM imatinib, 60 microg/ml mafosfamide and 14 days of culture with cytokines eliminated BCR-ABL(+) cells from chronic phase CML patient aphereses, while preserving normal progenitors. This novel purging strategy may offer a new approach to improving the effectiveness of autologous transplantation in imatinib-refractory CML patients.

Antigens, CD↗

PubMed2000

HLA-DR4 is associated with a diminished risk of the development of chronic myeloid leukemia (CML). Chronic Leukemia Working Party of the European Blood and Marrow Transplant Registry.

CML is characterized by the chromosomal translocation t(9;22) (q34;q11) resulting in the chimeric bcr-abl oncogene that encodes P210 fusion proteins with novel amino acid sequences in the breakpoint region. If these peptides derived from P210 are presented by HLA molecules on the cell membrane of leukemic cells an immunological response may occur. Recent studies using synthetic peptides identical to the bcr-abl fusion region revealed that some peptides are capable of binding to the class I molecules HLA-A2,-A3,-A11 and -B8 and the class II molecules HLA-DR1, -DR2, -DR3, -DR4 and -DR11. Moreover T cell responses have been induced against bcr-abl-derived synthetic peptides bound to some of these HLA molecules. For HLA class I, we have previously shown that individuals expressing HLA-A3 and -B8 have a diminished risk of development of CML. To assess a similar protective effect of class II molecules we performed a large multi-center study. This study compared the frequencies of HLA-DR1, -DR2, -DR3, -DR4 and -DR11 of patients with CML from the database of the EBMT (n = 1462) with unaffected individuals from the registry of Bone Marrow Donors Worldwide (n = 500 596). Patients and controls were matched per country. This analysis yielded significantly lower odds ratios (ORs) of 0.86 (95% CI 0.75-0.98) for HLA-DR3 and of 0.80 (95% CI 0.71-0.89) for HLA-DR4. The OR was 0.91 (95% CI 0.80-1.04) for HLA-DR1, 1.05 (95% CI 0.94-1.18) for HLA-DR2 and 0.87 (95% CI 0.74-1.01) for HLA-DR11. To assess a possible effect of the linkage disequilibrium between HLA-B8 and HLA-DR3 we found that coexpression of HLA-B8 and HLA-DR3 gave an OR of 0.84 (95% CI 0.72-0.98), whereas HLA-DR3 positive/HLA-B8 negative individuals showed an OR of 1.02 (95% CI 0.84-1.24). This means that the protective effect of HLA-DR3 of the development of CML was probably caused by its linkage disequilibrium with HLA-B8. In contrast, as there is no linkage disequilibrium of HLA-DR4 with HLA-A3 or HLA-B8, the results indicate that HLA-DR4 expression itself is associated with a diminished incidence of CML possibly by the presentation of bcr-abl breakpoint peptides in these HLA molecules on the membrane of the leukemic cells.

Bone Marrow Transplantation↗