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Background and Aims: The simultaneous measurement of many proteins is now possible using multiplex assays. In this pilot study we investigated a total of 124 proteins in plasma from chronic myeloid leukemia (CML) patients with the purpose of identifying proteins that are differently expressed at diagnosis and after tyrosine kinase inhibitor (TKI) treatment initiation., Methods: Samples were taken from 14 CML patients at diagnosis and after three months of TKI treatment (imatinib or dasatinib). Samples were analyzed by Mesoscale Discovery, Myriad RBM MAP technology and Olink Proseek., Results: Multiple plasma proteins were differentially expressed before and after initiation of TKI therapy. Protein patterns demonstrated a possible shift towards Th1-immunity and reduced angiogenic stimuli. Further, some plasma proteins were identified that can be of potential interest to study further for biologic, prognostic or therapeutic significance such as E-selectin, uPAR, growth hormone and carbonic anhydrase IX., Conclusions: Plasma proteomics seems feasible and useful in CML patients, both for studying patterns of protein expression and for identifying single proteins differentially expressed before and after treatment. Plasma proteomics may be useful to map disease activity and biological processes. Hence, plasma proteomics can be used to understand drug mechanisms and treatment responses in CML., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The main objective of this study was to outline key characteristics, including health-related quality of life (HRQOL) and symptoms, in 175 chronic myeloid leukemia (CML) patients reporting intentional or unintentional reasons for not fully adhering to imatinib therapy. There was a significant higher proportion of males in the unintentional group (P = 0.037). Also, in this group patients were on average younger (P = 0.046). Patients reporting intentional reasons had generally a worse HRQOL profile and a higher symptom severity than those who reported unintentional reasons for non-adherence. This study suggests that patients with suboptimal adherence are not a homogenous group, thus generalized approaches to improve medication-taking behaviors are not recommended., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The increased survival associated with treatments for CML emphasize the importance of understanding the HRQOL of newly diagnosed and previously treated CML patients with all phases of disease. Functional Assessment of Cancer Therapy-Leukemia results from a phase 3 and a phase 2 trial are reported for over 900 1st, 2nd, 3rd line CP, AP, and BP patients. Physical Well-being and Leukemia symptoms were worse for patients in later lines of therapy. Individuals with AP and BP CML had poorer HRQOL than individuals with CP CML. HRQOL of CML patients was predominantly consistent with the longitudinal clinical trajectory of the disease., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

In vitro studies have suggested that imatinib may be toxic to cardiac myocytes. Though retrospective studies have not shown clinical heart failure, these did not look for subtle cardiac damage. We have carried out a prospective cardiac assessment in 59 chronic myeloid leukaemia (CML) patients treated with imatinib for a median of 3.4 years, using echocardiography and MUGA scanning, with the latter repeated after a further year. We report no evidence of myocardial deterioration, either at baseline or over 12 months of imatinib treatment. Imatinib cardiotoxicity is not an important clinical consideration for CML patients or their advisors., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

A 40-year old patient with small cell lung cancer (SCLC) was treated with combined modalities including high-dose chemotherapy with subsequent autologous peripheral blood progenitor cell transplantation plus adjuvant radiotherapy. He achieved complete remission with regards to the primary disease. After an interval of 28 months, he was diagnosed with chronic myelogenous leukemia (CML). Analysis of graft samples at time of primary treatment for SCLC using polymerase chain reaction (PCR) did not show the bcr-abl transcript characteristic for CML. This case supports the observation that CML can develop as a treatment-related malignancy and gives insight in the length of the preclinical phase of the disease.

The retinoblastoma tumor suppressor (Rb) gene product plays an essential role in cell-cycle regulation. However, its role in terminal differentiation of hematopoietic cells is speculative. Here we show a model of 12-o-tetradecanoylphorbol-13-acetate (TPA)-induced hematopoietic differentiation and growth arrest with a defective Rb-mediated pathway. TPA treatment arrested the cell cycle of a human hematopoietic cell line, MEG-01s, at the G1-S boundary and induced expression of p21/SDI1/WAF1/CIP1 and p27/KIP1. Both of these proteins were present in cyclin E-associated complexes, the histone H1 and Rb kinase activities of which were then inactivated. However, MEG-01s cells lacked the intact Rb protein and the Rb-mediated pathway was defective. This model raises a question about the role for Rb in terminal differentiation of hematopoietic cells.

Macrophage inflammatory protein-1 alpha (MIP-1 alpha) is a negative regulator of normal haemopoietic stem cell proliferation. Insensitivity to MIP-1 alpha of progenitor cells in chronic myeloid leukaemia (CML) could, therefore, explain myeloid expansion in this disease. We compared the effects of MIP-1 alpha on progenitor cells in normal marrow and in the blood and marrow of patients with chronic phase CML. Plastic-adherent precursors of granulocyte-macrophage colony-forming cells (P delta progenitors) are very primitive progenitor cells and are detected by incubating them for 1 week in liquid culture and assaying the CFU-GM released into the supernatant. Direct CFU-GM assays were also used in this study. Daily addition of 300 ng/ml/day of MIP-1 alpha to P delta progenitor assays of normal marrow cells suppressed CFU-GM production by 50% and in CML bone marrow P delta cultures by 20-30%. The response of CML blood P delta progenitors was heterogeneous. In five of nine cases, CFU-GM production was doubled in the presence of MIP-1 alpha and in four of nine cases, it was reduced. Addition of 100-500 ng MIP-1 alpha to direct assays of CFU-GM stimulated colony formation by normal marrow and CML blood cells to a similar extent.

The clinical importance of CML lies in its poor responsiveness to chemotherapy which has proved highly effective in treating ALL. The scientific importance of CML resides in its role as a cancer prototype, permitting the identification of genes centrally involved in both neoplastic change and normal cellular differentiation. One of these genes, the fusion gene BCR/ABL resulting from the balanced translocation (9;22) has received wide attention owing to its intimate involvement in CML. Although a tremendous amount of data have been recently discovered about BCR/ABL, its exact role in leukemogenesis and normal hematopoiesis remains obscure. The study of CML cell lines has already been of considerable help in understanding the molecular events associated with the Ph chromosome [4]. Further advances are likely to be forthcoming, particularly at the molecular genetic, but also at the protein level. CML cell lines may offer an excellent means of addressing many issues as continuous cell lines represent an inexhaustible source of identical cell material that, in addition, can be made available to other researchers around the world. This overview on the thus far reported CML-derived cell lines supports the hypothesis that in some specimens of CML the target cells in which Ph translocation arises are not necessarily lineage-restricted committed progenitor cells, but are in fact in some (or all?) cases precommitted bipotential or multipotential progenitor or stem cells retaining the potential for differentiation in diverse hematopoietic directions [26]. In conclusion, established tumor cell lines with their unique phenotypic and karyotypic features have been extremely useful models for investigation of the molecular and biological characteristics of CML. Considerable progress in understanding the molecular and cell biology of CML has been achieved. Further advances in the knowledge of CML are expected to accrue with the productive use of these powerful research tools for many important unresolved issues. By so doing, these discoveries might open new avenues that promise to move clinicians closer to the goal of the prevention or cure of CML in all patients.

The bone-marrow microenvironment has a decisive role in maintaining haemopoietic stem cells and regulating their differentiation. In diseases of the haemopoietic system, viz. anaemias and leukemias, the microenvironment has been shown to play a key role. In this paper we show that leukemic cell conditioned medium and sera from CML patients, interact with the in vitro bone-marrow environment and bring about changes which affect the maintenance of normal stem cells.

The chemotactic index (C.I.) of granulocytes from chronic myeloid leukemia (CML) patients at diagnosis and in subsequent remission was measured using different concentrations of the synthetic chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine (FMLP), by time lapse cinematography and compared with that of normal granulocytes. The C.I. of CML polymorphonuclear leucocytes (PMNL) at diagnosis and in remission was significantly lower than the C.I. of PMNL from normal subjects (p less than 0.001 and 0.05 greater than p greater than 0.02, respectively). PMNL from CML patients at diagnosis showed increased speed after stimulation with FMLP. In most of the CML patients, the highest values of C.I., speed and the number of motile cells were obtained at FMLP concentrations of 10-100-fold higher than those required for normal PMNL. These results suggest an alteration in the interaction between FMLP and its receptors and that events occurring after FMLP binding are also altered. It was earlier shown that PMNL from CML patients in the active stages of the disease show defective chemotaxis. Present studies show persistence of such defective cells in the peripheral blood of CML patients in remission. These results also suggest that defects in PMNL from CML patients in remission. These results also suggest that defects in PMNL from CML patients may be constitutional.