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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    • "JID: MBS [m5G;September 21, 2015;20:38] [49]. Typically CML endures a transition from a slower chronic phase to a faster accelerated phase [48] [49]. Our model suggests that this behavior could be explained if tumor growth is first dominated by the growth rate of differentiated cells (chronic phase), and then by the growth rate of stem cells (accelerated phase). "
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    ABSTRACT: Healthy human tissue is highly regulated to maintain homeostasis. Secreted negative feedback factors that inhibit stem cell division and stem cell self-renewal play a fundamental role in establishing this control. The appearance of abnormal cancerous growth requires an escape from these regulatory mechanisms. In a previous study we found that for non-solid tumors if feedback inhibition on stem cell self-renewal is lost, but the feedback on the division rate is still intact, then the tumor dynamics are characterized by a relatively slow sub-exponential growth that we called inhibited growth. Here we characterize the cell dynamics of inhibited cancer growth by modeling feedback inhibition using Hill equations. We find asymptotic approximations for the growth rates of the stem cell and differentiated cell populations in terms of the strength of the inhibitory signal: stem cells grow as a power law t(1/k+1), and the differentiated cells grow as t(1/k), where k is the Hill coefficient in the feedback law regulating cell divisions. It follows that as the tumor grows, undifferentiated cells take up an increasingly large fraction of the population. Implications of these results for specific cancers including CML are discussed. Understanding how the regulatory mechanisms that continue to operate in cancer affect the rate of disease progression can provide important insights relevant to chronic or other slow progressing types of cancer.
    Mathematical biosciences 09/2015; DOI:10.1016/j.mbs.2015.08.009 · 1.30 Impact Factor
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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(2):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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