P119

Q3 Medicine Ejc Supplements Pub Date : 2015-11-01 DOI:10.1016/j.ejcsup.2015.08.028
R. Fadeev , M. Solovieva , S. Zakharov , I. Fadeeva , A. Senotov , A. Golenkov , V. Akatov
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引用次数: 0

Abstract

Acute myelomonocytic leukemia (FAB M4) is one of the most common forms of acute myeloid leukemia (AML). This AML form is characterized by rapid accumulation transformed myeloblasts and monoblasts in bone marrow, with the rapid suppression of normal hematopoiesis. Bone marrow microenvironment is one of the main factors determining drug resistance of leukemic cells. It is known that the adhesion of leukemic cells to mesenchymal stem cell and bone marrow extracellular matrix (laminin, collagen) enhances their drug resistance. However, it remains unknown whether the emergence of drug resistance when cell–cell contacts are formed only between leukemia cells, without the involvement of bone marrow stromal elements. We studied the role of cell aggregation in drug resistance of leukemic cells. We used the bone marrow mononuclear cells (BMMC) isolated from the patients with acute myelomonocytic leukemia. For the formation of multicellular aggregates, BMMC were cultivated in 96-well plates coated with 1.5% agarose. We showed that resistance of BMMC to bortezomib, doxorubicin and fludarabine in multicellular aggregates was increased. In three-dimensional multicellular aggregates of BMMC index IC50 for bortezomib, doxorubicin and fludarabine was 7 ± 1 ng/ml, 1 ± 0.4 mkM and 0.8 ± 0.05 mkM, respectively. In control condition, index IC50 bortezomib, doxorubicin and fludarabine was significantly lower, 2 ± 0.5 ng/ml, 0.3 ± 0.05 mkM and 0.07 ± 0.001 mkM, respectively. In multicellular aggregates of BMMC number of mitotic cells and expression of Ki-67 protein were not significantly different from the control. It has also been shown that cells in multicellular aggregates increased expression antiapoptotic protein Bcl-2. Suppression of BMMC aggregation by culturing the cells in medium containing 0.9% methylcellulose resulted in decreased IC50 index for bortezomib, doxorubicin and fludarabine, 2 ± 0.7 ng/ml, 0.12 ± 0.004 mkM and 0.04 ± 0.005 mkM, respectively. Expression of the Bcl-2 protein was also decreased. This work demonstrates the involvement of cell aggregation in the formation of drug resistance phenotype in leukemic cells.

The work was supported by the Russian Foundation for Basic Research (Russia) (No. 14-04-32183, 14- 04-32191), the scholarship of the President of the Russian Federation (Russia) (No. SP-6867.2013.4, SP-1519.2015.4), and by the Government of the Russian Federation (Russia) (No.14.Z50.31.0028).

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P119
急性髓单细胞白血病(FAB M4)是急性髓系白血病(AML)最常见的形式之一。这种AML形式的特点是骨髓中转化成髓细胞和单细胞的快速积累,正常造血功能迅速受到抑制。骨髓微环境是决定白血病细胞耐药的主要因素之一。众所周知,白血病细胞与间充质干细胞和骨髓细胞外基质(层粘连蛋白、胶原蛋白)的粘附增强了它们的耐药性。然而,当细胞-细胞接触仅在白血病细胞之间形成,而不涉及骨髓基质元件时,是否会出现耐药性尚不清楚。我们研究了细胞聚集在白血病细胞耐药中的作用。我们采用从急性髓单细胞白血病患者中分离的骨髓单核细胞(BMMC)。为了形成多细胞聚集体,将BMMC培养在涂有1.5%琼脂糖的96孔板上。我们发现BMMC对硼替佐米、阿霉素和氟达拉滨的多细胞聚集体耐药性增加。硼替佐米、阿霉素和氟达拉滨的三维多细胞聚集体BMMC指数IC50分别为7±1 ng/ml、1±0.4 mkM和0.8±0.05 mkM。对照条件下,硼替佐米、阿霉素和氟达拉滨的IC50指数显著降低,分别为2±0.5 ng/ml、0.3±0.05 mkM和0.07±0.001 mkM。在BMMC多细胞聚集体中,有丝分裂细胞数量和Ki-67蛋白的表达与对照组无显著差异。研究还表明,多细胞聚集的细胞增加了抗凋亡蛋白Bcl-2的表达。在含0.9%甲基纤维素的培养基中培养细胞抑制BMMC聚集,硼替佐米、阿霉素和氟达拉滨的IC50指数分别降低了2±0.7 ng/ml、0.12±0.004 mkM和0.04±0.005 mkM。Bcl-2蛋白的表达也降低。这项工作证明了细胞聚集参与白血病细胞耐药表型的形成。俄罗斯基础研究基金会(No. 14-04-32183, 14- 04-32191)、俄罗斯联邦总统奖学金(No. 14- 04-32191)资助。SP-6867.2013.4, SP-1519.2015.4),俄罗斯联邦政府(俄罗斯)(No.14.Z50.31.0028)。
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来源期刊
Ejc Supplements
Ejc Supplements 医学-肿瘤学
自引率
0.00%
发文量
0
审稿时长
3.7 months
期刊介绍: EJC Supplements is an open access companion journal to the European Journal of Cancer. As an open access journal, all published articles are subject to an Article Publication Fee. Immediately upon publication, all articles in EJC Supplements are made openly available through the journal''s websites. EJC Supplements will consider for publication the proceedings of scientific symposia, commissioned thematic issues, and collections of invited articles on preclinical and basic cancer research, translational oncology, clinical oncology and cancer epidemiology and prevention. Authors considering the publication of a supplement in EJC Supplements are requested to contact the Editorial Office of the EJC to discuss their proposal with the Editor-in-Chief. EJC Supplements is an official journal of the European Organisation for Research and Treatment of Cancer (EORTC), the European CanCer Organisation (ECCO) and the European Society of Mastology (EUSOMA).
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