The occurrence of variant Ph translocations in chronic myeloid leukemia (CML): a report of six cases

Variants of Philadelphia chromosome (Ph) translocation were detected in six of 95 Ph positive chronic myeloid leukemia (CML) patients (6.3 per cent). Two of these patients showed a Ph variant of 'simple' type, involving chromosomes 10 and 12. In four patients, the variant Ph was of 'complex' type involving a third chromosome:chromosomes 1, 6, 7 and 12 in addition to 9 and 22. Two of these resulted in the occurrence of a 'masked' Ph. In addition to variant Ph translocations, variant breakpoints such as q12 (two patients) and q13 (one patient) on chromosome 22 were observed in another three patients with t(9;22).     

Eosinophilic variant of chronic myeloid leukemia with vascular complications

Eosinophilic variant of CML (eoCML) is a unique disease with a poor prognosis. Like the hypereosinophilic syndrome (HES), eoCML has no clinically identifiable reason for an increased eosinophil count in the peripheral blood. In contrast to HES, eoCML patients carry a distinct chromosomal abnormality. The bcr/abl fusion gene (Philadelphia chromosome) is the genetic basis of this clonal disease. Recently, eoCML has been separated from HES. Patients with eoCML frequently suffer organ damage including the heart and lungs. This damage is related to the release of eosinophilic granules in the blood, which results in fibrosis of the endothelial lining. We report a case of a peripheral vasculitis complicated by gangrene of the fingers in a patient with eoCML. Despite an almost complete response to CML treatment with Gleevac, combined with prednisone, aspirin and coumadin the patient sustained irreversible damage to the vascular lining of the distal arteries of the upper extremities.     

Multilineage cell involvement in Ph1-negative, bcr-negative chronic myeloid leukemia

We report a case of Ph1-negative, bcr-negative CML-BC, in which the primary leukemic cells displayed T-related antigens (CD7, CD4) in addition to HLA-DR and CD25 determinants. No B-lymphoid, myeloid and megakaryoblastic surface antigens were detected. In spite of this phenotype, DNA analysis revealed a germ-line configuration of the T-cell receptor beta chain gene region. Moreover, in-vitro culture studies demonstrated a proliferative response of the blast cell population to natural and recombinant myeloid-related factors, while no proliferative signal was observed in the presence of IL-2. The myeloid lineage was further demonstrated by the expression of myeloid-associated antigens on cultured blast cells, which still retained the CD7 antigen. Finally, cytogenetic analysis revealed a monosomy 7 which is usually associated with a stem cell leukemia. These results support the hypothesis that Ph1-negative, bcr-negative CML is characterized by the involvement of a multipotent stem cell capable of multilineage expression and indicate that differentiative and proliferative assays provide a further tool towards a more precise recognition of hematological disorders of uncertain origin.     

BCR translocation to derivative chromosome 2: a new case of chronic myeloid leukemia with a complex variant translocation and Philadelphia chromosome

The well-known typical fusion gene BCR/ABL is observed in connection with a complex translocation event in 5-8% of cases of chronic myeloid leukemia (CML). The present study described an exceptional CML case with complex chromosomal aberrations not previously observed. Aberrations included a translocated BCR to the derivative chromosome 2 [der(2)] that also involved a four-chromosome translocation, implying chromosomal regions 1p32 and 2q21, besides 9q34 and 22q11.2, which were characterized by molecular cytogenetics.     

Involvement of chromosome 9 in variant Ph1 translocation

Cytogenetic analysis of a patient with chronic myelocytic leukemia revealed a translocation (21; 22) (q 22; q 11) without a detectable involvement of chromosome 9. By in-situ hybridization studies, however, we demonstrate a reciprocal translocation of sequences from chromosome 9 (c-abl) to Ph1 and chromosome 22 (bcr) to 9, respectively. These observations suggest a consistent participation of chromosome 9 in the Ph1 translocation, regardless of the cytogenetic subtype.     

PDGFRB基因易位的不典型慢性髓细胞白血病的临床观察

目的 探讨涉及PDGFRB基因易位的不典型慢性髓细胞白血病(CML)的诊断和治疗.方法 对1例不典型CML患者进行骨髓细胞染色体核型分析,RT-PCR检测bcr/abl融合基因,荧光原位杂交(FISH)检测PDGFRB基因易位,羟基脲和干扰素治疗并观察疗效.结果 该例患者的骨髓细胞染色体核型为46,XY,t(5;12)...     

Complex translocation involving four chromosomes in a novel Philadelphia-positive chronic myeloid leukemia case

The so-called Philadelphia (Ph) chromosome is present in more than 90% of chronic myeloid leukemia (CML) cases. Approximately 5-10% of these patients show complex translocations involving a third chromosome in addition to chromosomes 9 and 22. Since the majority of CML cases are currently treated with imatinib, variant rearrangements in general have no specific prognostic significance, although the mechanisms involved in resistance to therapy have yet to be investigated. This study evalutated a CML case with complex chromosomal aberrations not previously observed. A four chromosome translocation involving chromosomal regions such as 12q24.2-24.31 and 16p11.2 besides 9q34 and 22q11 were characterized in detail by array-proven multicolor banding (aMCB). A beneficial response to imatinib was noted in the patient.     

BCR-ABL-negative chronic myeloid leukemia

Constitutive activation of protein tyrosine kinases plays a central role in the pathogenesis of myeloproliferative disorders, including BCR-ABL-negative chronic myeloid leukemia. Current research is focused on elucidating the full spectrum of causative mutations in this rare, heterogeneous disease. Activated tyrosine kinases are excellent targets for signal transduction therapy, and an accurate diagnosis including morphology, karyotyping, and molecular genetics will become increasingly important to direct individualized treatment. In addition, new molecular findings need to be incorporated into disease classification systems.     

Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia

Although mast cells (MC) play an important role in allergic reactions, their physiologic role remains unknown. In mice, several models of MC-deficiency have been developed. However, no comparable human model is available. We examined the in vitro- and in vivo effects of the KIT-targeting drug imatinib on growth and development of human MC. Imatinib was found to inhibit stem cell factor (SCF)-induced differentiation of MC in long-term suspension cultures (IC50: 0.01 μM). Correspondingly, long-term treatment of chronic myeloid leukemia (CML) patients with imatinib (400 mg/day) resulted in a marked decrease in MC. In patients with continuous complete molecular response during therapy, bone marrow MC decreased to less than 5% of pre-treatment values, and also serum tryptase concentrations decreased significantly (pre-treatment: 32.0±11.1 ng/ml; post-therapy: 3.4±1.8, p<0.01). Other myeloid lineages, known to develop independently of KIT, were not affected by imatinib-therapy. Imatinib also produced a substantial decrease in MCdevelopment in mice. However, no clinical syndrome attributable to drug-induced MC-deficiency was recorded in our CML patients. Together, imatinib suppresses MC production in vitro and in vivo. However, drug-induced MC depletion is not accompanied by adverse clinical events, suggesting that MC are less relevant to homeostasis in healthy tissues than we assumed so far.     

慢性粒细胞白血病的治疗进展

Bcr/Abl酪氨酸激酶抑制剂作为分子靶向治疗药物用于慢性粒细胞白血病(CML)的治疗,大大提高了血液学缓解率和遗传学缓解率,且在聚乙二醇干扰素(IFN)、非清髓造血干细胞移植(HSCT)、树突状细胞疫苗等治疗方面也取得了新进展.临床研究表明,以酪氨酸激酶抑制剂为基础的联合治疗更加有效.     

Models of chronic myeloid leukemia

Models of chronic myeloid leukemia (CML) have proven invaluable for furthering our understanding of the molecular pathophysiology of this disease. Xenotransplantation of primary human CML cells into immunodeficient mice allows investigation into the nature of the most primitive repopulating cells in this leukemia, but the system is limited by variability and difficulty with experimental manipulation. Accordingly, a large effort has been invested in developing models of CML through expression of the BCR/ABL oncogene in the hematopoietic system of laboratory mice. Despite numerous attempts, an accurate transgenic mouse model of CML has not been produced, possibly because of the toxicity of BCR/ABL. Conditional transgenic mice are a promising new approach to this problem. A more successful strategy is retroviral transduction of BCR/ABL into mouse bone marrow in vitro, followed by transplantation into syngeneic or immunodeficient recipient mice. Recipients of marrow transduced with p210 BCR/ABL develop a fatal myeloproliferative illness that closely resembles human CML. This model is being used to define the signaling pathways required for leukemogenesis by BCR/ABL, and for developing new therapeutic approaches.     

慢性粒细胞白血病端粒酶的相关研究

目的：对慢性粒细胞白血病端粒酶进行研究,采用 PCR －ELISA 半定量法测定端粒酶活性,同时观察端粒酶活性变化的相关性。方法：选取15例慢性粒细胞白血病患者骨髓标本和15例正常骨髓（取自非肿瘤病人需行骨髓检查者）样本分为慢性粒细胞白血病组（CML 组）和正常对照组,采用 PCR －ELISA 法来测定CML 组和正常对照组的端粒酶活性。结果：正常对照组端粒酶具有微弱的活性,而 CML 组则具有较强的活性,且端粒酶活性 CML 组高于正常对照组,两者差异性非常显著。其中,CML 组男性与女性组间端粒酶活性差异无统计学意义。结论：正常组端粒酶具有微弱的活性,而 CML 组则具有较强的活性。端粒酶活性可能反映了一个高度增生的状态,是一种新的肿瘤标记物,与肿瘤发生密切相关。     

Targeted therapy in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is characterized by the formation of the Philadelphia chromosome and oncogenic signaling by the resulting Bcr-Abl fusion protein. Understanding the molecular basis of CML has led to the development of highly effective targeted therapies that block Bcr-Abl tyrosine kinase activity. Imatinib, the current first-line therapy for CML, induces durable treatment responses in most patients. However, patients may develop imatinib resistance, which is often due to BCR-ABL mutations. With the availability of second generation tyrosine kinase inhibitors, an effective therapeutic option other than stem cell transplantation is available following imatinib failure. Randomized trial data suggest that dasatinib treatment is superior to imatinib dose escalation in patients with imatinib resistance. Nilotinib, a recently approved analogue of imatinib, has also demonstrated encouraging treatment responses in patients with imatinib-resistant CML. Other agents (including bosutinib and INNO-406) are in clinical development. With the potential availability of multiple treatment options for patients with CML, it may be possible to tailor treatment according to individual patient or disease characteristics, for example, BCR-ABL mutations. Future CML treatment may involve combination strategies. Overall, targeted agents have significantly improved the prognosis of patients diagnosed with CML.     

Immunotherapeutic strategies in chronic myeloid leukemia

Several clinical observations demonstrate that immunologic effects are important in chronic myeloid leukemia (CML). The characteristic BCR-ABL fusion protein is a leukemia-specific antigen, and it has therefore received much immunologic attention, especially regarding the amino acid sequences that span the e14a2 junction. Other attractive targets are the Wilms’ tumor 1 antigen and the PR1 epitope from proteinase 3, a granule protein overexpressed in CML. Imatinib may modulate several components of the immune response, although the clinical relevance of this effect is uncertain. In clinical trials, peptide vaccination appears safe and undoubtedly produces clinical effects, but randomized trials are now required to see if these are distinct from the effects of other concurrent therapy. These trials will be difficult to orchestrate in the competitive environment of novel therapies for CML.