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1Gene Expression Upon Proliferation and Differentiation of Hematopoietic Cells with PH Chromosome Ex Vivo

N I Grineva,E A Duchovenskay,A M Timofeev,T V Akhlynina,L P Gerasimova,T V Borovkova, D A Schmarov, N G Sarycheva, N M Naydenova,A R Gavrichkova,L Y Kolosova,T I Kolosheynova,

The genesp53, mdm2, p21, c-myc,bcr/abl, bcr, bcl2, bax, and gapdh participate in the regulation of cell proliferation and differentiation, apoptosis and cell distribution for the cell cycle ex vivo in the Ph(+)cells of chronic myeloid leukemia containing the Ph chromosome andbcr/abloncogene. Expression of these genes correlates with regulation of cell proliferation and differentiation by alternating proliferation and maturation stages for three main Ph+cell types that occur under chronic myeloid leukemia. Thep53, p21, mdm2, and gapdh genes overexpress in active proliferating myeloid cells in the cell cycle S+ G2/M phases and when the phases are coincident with the proliferation stage. Expression of these genes decreases to a considerable level under alternation of the Ph(+)cell proliferation and maturation stages and whenever the expression is greatly diminished under significant neutrophil accumulation and especially under repeated alternation of the stages. In the course of neutrophil maturation, gene expression levels decrease in the range of gapdh > actin > c-myc, bcr/abl,p21 > p53 > bcl2 > bax.The expression levels of these genes in neutrophils are lower than those in myelocytes and lower by an order of magnitude than that in the cells with a prolonged proliferation stage. TheBcr/ablexpression gene under prolonged maturation and neutrophil accumulation is inhibited; however it is enhanced by 2-3 times for the proliferation stage with myelocyte accumulation. Minimalbcr/ablexpression is observed under overexpression ofp53, mdm2, p21, c-myc,as well as under cell maximum at the S and G2/M phases. Bcr/abloverexpression is observed under low expression of thep53, p21, mdm2genes. In the Ph(+ )cells with a high P/D efficiency index (5-20), overexpression of the genes in the range ofbcr> gapdh>bcr/abl, as well as a decreased expression of thep53, bcl2, mdm2, p21<< gapdh genes is observed for Ph(+)cells from the CML blast crisis and CML acceleration phase. Low control of cell proliferation and cell cycle by gene-regulators presumably promotesbcr/abloverexpression and activаtes the production ofbcr/abl+ cells. Apoptosis in the Ph(+ )cells is induced by expression of thebax > bcl2, р53, p21, c-myc andgapdhgenes. The blocking of Ph(+)cell apoptosis, neutrophil accumulation, and decrease in the expression of the p53, mdm2 and p21, c-myc,bcr/abl genes occur at the maturation stage.

2012Acta naturae（2012）引用：6

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2ЭКСПРЕССИЯ ГЕНОВ ПРИ ПРОЛИФЕРАЦИИ И ДИФФЕРЕНЦИРОВКЕ ГЕМОПОЭТИЧЕСКИХ КЛЕТОК С PH-ХРОМОСОМОЙ EX VIVO

н и гринева, е а духовенская,а м тимофеев,т в ахлынина,л п герасимова,т е манакова,т в боровкова,д а шмаров,т г сарычева,н м найденова,а р гавричкова,л ю колосова,

2012引用：23

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3Различия В Пролиферации И Дифференцировке Ph+клеток От Индивидуальных Больных ХМЛ В Суспензионной Культуре: 3. Ph+клетки С Чередованием Этапов Эффективной Пролиферации И Эффективного Созревания

Гринева Нина Ивановна,Т В Ахлынина, Л П Герасимова, Tereza Maňáková,Т Г Сарычева,Д А Шмаров, А. М. Тимофеев,Н М Найденова,Г П Саркисян,Т В Боровкова,А Р Гавричкова,Л Ю Колосова,

2010Российский биотерапевтический журнал

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4РАЗЛИЧИЯ В ПРОЛИФЕРАЦИИ И ДИФФЕРЕНЦИРОВКЕ PH+КЛЕТОК ОТ ИНДИВИДУАЛЬНЫХ БОЛЬНЫХ ХМЛ В СУСПЕНЗИОННОЙ КУЛЬТУРЕ. PH+КЛЕТКИ С НИЗКОЙ ЭФФЕКТИВНОСТЬЮ ПРОЛИФЕРАЦИИ И СПОСОБНОСТЬЮ БЛОКИРОВАТЬ АПОПТОЗ

т в ахлынина,н и гринева,л п герасимова,т е манакова,д а шмаров,т г сарычева,а м тимофеев,н м найденова,т в боровкова,г п саркисян,а р гавричкова,л ю колосова,

2010引用：23

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5Различия В Пролиферации И Дифференцировке Ph+клеток От Индивидуальных Больных ХМЛ В Суспензионной Культуре. Ph+клетки С Низкой Эффективностью Пролиферации И Способностью Блокировать Апоптоз

Т. В. Ахлынина, Гринева Нина Ивановна,Л. П. Герасимова,Т. Е. Манакова,Д А Шмаров, Tatyana Sarycheva,А. М. Тимофеев,Н. М. Найденова,Т. В. Боровкова,Г П Саркисян,А Р Гавричкова,L. I. Kolosova,

Three types of Ph +cells from individual CML patients have been detected by studying kinetics peculiarities of their proliferation and differentiation in the culture [7]. Here we have studied the proliferation and differentiation of type 2 Ph +cells that reveal low proliferating P/D efficiency and higher rate for accumulation of neutrophiles maturated without dividing. P/D index is ratio between rates for P and D cells accumulations. Proliferation and differentiation of type 2 Ph +cells reveal P/D index 0,2-1, number of cycling cells into cycle phases S+G2/M was below 20÷45%. The proliferation and differentiation of Ph + type 2 cells is accompanied by apoptosis inhibition and significant accumulation of neutrophils, particularly high segment neutrophils, we have also observed the reduced proliferation of Ph + cells and low content of myelocytes. Apoptosis blocking and maturated neutrophiles accumulation occur anisochrous myelocytes accumulation but synchronously proliferation inhibition. This results in neutrophils primary consistency inversion myelocytes (M) > metamyelocytes (MM) > band neutrophiles (BN)> segment neutrophieles (SN) into SN > BN > MM > M, which lead to accumulation of al types neutrophils. These peculiar properties of Ph + type 2 cells determine the cells proliferation and differentiation in parallel with inhibition of neutrophils maturation. We suggest this take place by feed back mechanism. The curves of Ph + type 2 leukocytes population accumulating do not reflect the proliferation rate of Ph + type 2 leukocytes. The increased level of these cells we link with the increasing number of maturated neutrophils and their non-efficient proliferation. Ph + type 2 cells account for one-third fraction of investigated Ph+ cells. We have derived all of cells from patient with CML in a quite phase.

2010Российский биотерапевтический журнал

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6РАЗЛИЧИЯ В ПРОЛИФЕРАЦИИ И ДИФФЕРЕНЦИРОВКЕ PH+КЛЕТОК ОТ ИНДИВИДУАЛЬНЫХ БОЛЬНЫХ ХМЛ В СУСПЕНЗИОННОЙ КУЛЬТУРЕ: 3. PH+КЛЕТКИ С ЧЕРЕДОВАНИЕМ ЭТАПОВ ЭФФЕКТИВНОЙ ПРОЛИФЕРАЦИИ И ЭФФЕКТИВНОГО СОЗРЕВАНИЯ