Cell Regulation of Proliferation and Differentiation ex vivo for Cells Containing Ph Chromosome in Chronic Myeloid Leukemia

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Cell regulation of Ph +cell proliferation and differentiation has been studied ex vivo in various chronic myeloid leukemia (CML) patients. The regulation is provided by alternation of effective stages of proliferation and maturation with inhibition of Ph+ cell proliferation by accumulating neutrophils under apoptosis blockage. The alternation of stages consists of switching stage 1 (effective proliferation) to stage 2 (effective maturation) and proceeds according to the 1/2 -1/2/1 or 2/1-2/1/2/1 schemes. The kinetic plots of alternations pass through control points of crossing plots, where the parameters of proliferation and maturation are equal. The indices of P/D efficiency (ratio of proliferation and maturation rates) are 1.06±0.23 and don’t depend on time, alternation order, or sources of Ph+ cells – CML patients. During stages alternation, conversely, the parameters of Ph + cell proliferation and maturation vary. The proliferation stages are characterized by increased proliferating cells content, a decreased number of neutrophils, and apoptosis induction. At the maturation stages, conversely, apoptosis is inhibited, the number of mature neutrophils increases, while immature Ph + cells decrease. High content neutrophils inhibit the proliferation of Ph + cells and impair their own maturation by inversion of maturation order, probably through a feedback mechanism. The regulation differences ex vivo reveal three types of Ph + cells from various individual CML patients, distinguished by the number and duration of alternating stages of proliferation and maturation. Ph + cells types 1 and 2 have one prolonged stage of effective proliferation or effective maturation with efficiency indices P/D 1 = 1-20 or P/D 2 ≤ 1. At the same time period, the proliferation and differentiation of the Ph + cells type 3 proceeds with repeated alternations of stages with P/D 1 = 1-4 or P/D 2 ≤ 1. Type 1 Ph + cells (~20%) were isolated from patients in advanced stages of CML, while Ph + cells types 2 and 3 (30 and 50% correspondingly) were isolated from CML chronic phase patients sensitive to chemotherapy.

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Leukemias accounts for 1% of all deaths and 4-10% of deaths from cancer. The prevalence of leukemias and lymphomas varies from 3 to 9:100 000, depending on the geographical region. Unfavorable radiation and ecological environment can increase it by 1.5 logs. In the U.S., leukemias are the major reason of death in children before 15. The majority of leukemias result from genetic disturbances: chromosomal aberrations, translocations, inversions, deletions, and various mutations [1-3, 6]. Philadelphia-positive (Ph-) cells, expressing active tyrosine kinase р210 or р185 (oncoproteins, products of bcrabl gene), are involved in chronic myeloid leukemia (CML) pathogenesis. It results in reciprocal chromosomal translocation t(9;22)(q34;q11) in the polipotent hematopoietic stem cell. Proliferation and differentiation of this cell leads to replacement of normal hematopoietic cells by their monoclonal neoplastic Ph- counterparts, thus promoting the development and progress of CML [1- 8, 10, 12]. The CML clinical course varies among different patients. The cellular and molecular mechanisms of these differences remain unclear. Current knowledge of CML course and progression in vivo is based upon analyses of averaged values of various parameters obtained at different moments and CML phases. CML undergoes a chronic phase (CP), accelerated phase (AP), and an acute rapidly progressing blast phase (BP) with an inevitable fatal outcome. Current CML therapy is based upon highly specific targeted drugs, tyrosine kinase inhibitors (TKI), specifically blocking р210 – imatinib and its analogues. Imatinib allows to extend life by 6 years in 88% of patients., of which 66% continue treatment. In 14% of those patients, CML progresses, while 5% of them interrupt treatment because of toxicity. The toxicity is associated with additional bcr/abl gene mutations, leading to therapeutic resistance. Despite the development of a new generation of TKIs, the problem remains unsolved, because none of them kills the resting leukemia stem cells. Fewer than 5% of CML chronic phase patients are cured, while the majority eventually relapse [6]. There is a need for another strategy in dealing with leukemia stem cells.
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