The Biology of Chronic Myeloid Leukemia

Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
New England Journal of Medicine (Impact Factor: 55.87). 08/1999; 341(3):164-72. DOI: 10.1056/NEJM199907153410306
Source: PubMed
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    • "The blasts in CML-BP usually have myeloid phenotype, representing 70% of the cases. Approximately 30% of cases demonstrate lymphoblastic phenotype which is predominantly B-cell lineage [3, 4]. T-lymphoblastic BP of CML is very rare and so far approximately 50 cases have been reported in the English literature [5–9]. "
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    ABSTRACT: T-lymphoblastic leukemia/lymphoma (T-ALL) presenting as blast phase of chronic myelogenous leukemia (CML-BP) is rare. In patients without history of CML, it is difficult to differentiate between CML-BP or de novo T-ALL. Here we reported 2 unusual cases of T-ALL presenting as CML-BP. Case 1 was a 24-year-old female with leukocytosis. Besides T-lymphoblasts (32%), her marrow exhibited some morphologic features of CML. Multiple remission or relapsing marrow had never demonstrated morphologic features of CML. Despite of imatinib treatment and stem cell transplant, she died 2.5 years later. Case 2, a 66-year-old male with diffuse lymphadenopathy, showed T-ALL in a lymph node and concurrent CML chronic phase (CML-CP) in his marrow. Same BCR-ABL1 fusion transcript with minor breakpoint was present in both the lymph node and marrow specimens. Although both cases did not have a history of CML, both cases represented T-lymphoblastic CML-BP with unusual features: Case 1 is unusual in that it presented as T-ALL with some CML morphologic feature but never showed CML-CP in her subsequent marrows biopsies; Case 2 is the first reported case of T-lymphoblastic CML-BP harboring BCR-ABL1 transcript with a minor breakpoint.
    06/2014; 2014:304359. DOI:10.1155/2014/304359
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    • "Acute myeloid leukaemia (AML) is the third most common form of leukaemia in children, typically characterised by the rapid proliferation of primitive haematopoietic myeloid progenitor cells [1]. Paediatric AML is a highly heterogeneous disease, which presents a major barrier towards the development of accurate disease classification, risk stratification and targeted therapies within the clinic. "
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    ABSTRACT: Background Acute Myeloid Leukaemia (AML) is a highly heterogeneous disease. Studies in adult AML have identified epigenetic changes, specifically DNA methylation, associated with leukaemia subtype, age of onset and patient survival which highlights this heterogeneity. However, only limited DNA methylation studies have elucidated any associations in paediatric AML. Methods We interrogated DNA methylation on a cohort of paediatric AML FAB subtype M5 patients using the Illumina HumanMethylation450 (HM450) BeadChip, identifying a number of target genes with p <0.01 and Δβ >0.4 between leukaemic and matched remission (n = 20 primary leukaemic, n = 13 matched remission). Amongst those genes identified, we interrogate DLEU2 methylation using locus-specific SEQUENOM MassARRAY® EpiTYPER® and an increased validation cohort (n = 28 primary leukaemic, n = 14 matched remission, n = 17 additional non-leukaemic and cell lines). Following methylation analysis, expression studies were undertaken utilising the same patient samples for singleplex TaqMan gene and miRNA assays and relative expression comparisons. Results We identified differential DNA methylation at the DLEU2 locus, encompassing the tumour suppressor microRNA miR-15a/16-1 cluster. A number of HM450 probes spanning the DLEU2/Alt1 Transcriptional Start Site showed increased levels of methylation in leukaemia (average over all probes >60%) compared to disease-free haematopoietic cells and patient remission samples (<24%) (p < 0.001). Interestingly, DLEU2 mRNA down-regulation in leukaemic patients (p < 0.05) was independent of the embedded mature miR-15a/16-1 expression. To assess prognostic significance of DLEU2 DNA methylation, we stratified paediatric AML patients by their methylation status. A subset of patients recorded methylation values for DLEU2 akin to non-leukaemic specimens, specifically patients with sole trisomy 8 and/or chromosome 11 abnormalities. These patients also showed similar miR-15a/16-1 expression to non-leukaemic samples, and potential improved disease prognosis. Conclusions The DLEU2 locus and embedded miRNA cluster miR-15a/16-1 is commonly deleted in adult cancers and shown to induce leukaemogenesis, however in paediatric AML we found the region to be transcriptionally repressed. In combination, our data highlights the utility of interrogating DNA methylation and microRNA in combination with underlying genetic status to provide novel insights into AML biology.
    Molecular Cancer 05/2014; 13(1):123. DOI:10.1186/1476-4598-13-123 · 4.26 Impact Factor
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    • "Chronic myelogenous leukaemia (CML) is a clonal myeloproliferative disorder, characterized by presence of Philadelphia (Ph) chromosome [1]-[5], which is a reciprocal translocation t (9q34; 22q11) that creates an aberrant mRNA product, leading to production of a fusion protein p210 BCR-ABL that has a constitutive tyrosine kinase (TK) activity of ABL [6]-[8]. In the past, CML had been treated with busulfan and hydroxyurea but with high rates of progression from chronic to accelerated phase and median survival of 39 to 47 months [9]. "
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    ABSTRACT: Background: Treatment for Chronic Myeloid Leukaemia (CML) is mainly imatinib mesylate (IM) from original-brand, Glivec® or generic-type homologs, Imatib®. Materials and Methods: A collec- tion of 149 CML patients was treated over a period of 6 years at Hiwa hospital. These patients were clustered into three groups: Group A was treated with Imatib for more than one year. All sur- vivors of group A patients were switched to Glivec, classified as group B. Group C received only Glivec after June 2011. Imatib and Glivec are administered at doses 400-, 600- and 800-mg accor- ding to the CML stage. Results: Among group A patients, 68 (60%) were in complete haematologi- cal response (CHR), 32 (28.3%) developed acceleration and 13 (11.5%) patients were deceased. After switching to Glivec (group B), 69 (69%) patients remained in CHR, 10 (10%) patients were deceased and 21 (21%) patients remained in acceleration. Of the 36 patients in group C, 33 (91.7%) were in CHR, 1 (2.8%) were in acceleration and 2 (5.5%) deceased. Those patients with CHR were tested randomly for BCR/ABL by FISH, and only 1/25 (4%) patients were found with complete cy- togenetic response (CCyR) in group A, while 31/42 (73.8%) and 13/17 (76.5%) have CCyR in group B and C, respectively. Conclusions: Our results demonstrate a less cytogenetic response to treatment in patients of CML, who received the Imatib therapy, while a significant cytogenetic re- mission was found in patients with CHR after they switched to Glivec.
    Journal of Cancer Therapy 04/2014; 5(05):453-459. DOI:10.4236/jct.2014.55052
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