Romano Michela, Della Porta Matteo Giovanni, Gallì Anna, Panini Nicolò, Licandro Simonetta Andrea, Bello Ezia, Craparotta Ilaria, Rosti Vittorio, Bonetti Elisa, Tancredi Richard, Rossi Marianna, Mannarino Laura, Marchini Sergio, Porcu Luca, Galmarini Carlos M, Zambelli Alberto, Zecca Marco, Locatelli Franco, Cazzola Mario, Biondi Andrea, Rambaldi Alessandro, Allavena Paola, Erba Eugenio, D'Incalci Maurizio
Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, Milan, Italy.
Department of Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Br J Cancer. 2017 Jan;116(3):335-343. doi: 10.1038/bjc.2016.424. Epub 2017 Jan 10.
Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN.
Malignant CD14+ monocytes and CD34+ haematopoietic progenitor cells were isolated from peripheral blood/bone marrow mononuclear cells. The inhibition of CFU-GM colonies and the apoptotic effect on CD14+ and CD34+ induced by trabectedin were evaluated. Trabectedin's effects were also investigated in vitro on THP-1, and in vitro and in vivo on MV-4-11 cell lines.
On CMML/JMML cells, obtained from 20 patients with CMML and 13 patients with JMML, trabectedin - at concentration pharmacologically reasonable, 1-5 nM - strongly induced apoptosis and inhibition of growth of haematopoietic progenitors (CFU-GM). In these leukaemic cells, trabectedin downregulated the expression of genes belonging to the Rho GTPases pathway (RAS superfamily) having a critical role in cell growth and cytoskeletal dynamics. Its selective activity on myelomonocytic malignant cells was confirmed also on in vitro THP-1 cell line and on in vitro and in vivo MV-4-11 cell line models.
Trabectedin could be good candidate for clinical studies in JMML/CMML patients.
青少年粒单核细胞白血病（JMML）和慢性粒单核细胞白血病（CMML）是预后不良且无有效化疗方案的骨髓增生异常-骨髓增殖性（MDS/MPN）肿瘤。曲贝替定是一种DNA小沟结合剂，作为转录调节剂并干扰DNA修复机制；它可导致粒单核细胞系细胞的选择性耗竭。我们推测曲贝替定可能对MDS/MPN具有抗肿瘤作用。
从外周血/骨髓单个核细胞中分离出恶性CD14+单核细胞和CD34+造血祖细胞。评估曲贝替定对CFU-GM集落的抑制作用以及对CD14+和CD34+细胞的凋亡诱导作用。还在体外对THP-1细胞系以及在体外和体内对MV-4-11细胞系研究了曲贝替定的作用。
在从20例CMML患者和13例JMML患者获得的CMML/JMML细胞上，曲贝替定在药理合理浓度1-5 nM时，强烈诱导造血祖细胞（CFU-GM）凋亡并抑制其生长。在这些白血病细胞中，曲贝替定下调了Rho GTPases通路（RAS超家族）中对细胞生长和细胞骨架动力学起关键作用的基因的表达。其对粒单核细胞恶性细胞的选择性活性在体外THP-1细胞系以及体外和体内MV-4-11细胞系模型中也得到了证实。
曲贝替定可能是JMML/CMML患者临床研究的良好候选药物。
