Buchner Maike, Park Eugene, Geng Huimin, Klemm Lars, Flach Johanna, Passegué Emmanuelle, Schjerven Hilde, Melnick Ari, Paietta Elisabeth, Kopanja Dragana, Raychaudhuri Pradip, Müschen Markus
Department of Laboratory Medicine, University of California San Francisco, San Francisco, California 94143, USA.
1] Department of Laboratory Medicine, University of California San Francisco, San Francisco, California 94143, USA [2] Department of Haematology, University of Cambridge, Cambridge CB2 OAH, UK.
Nat Commun. 2015 Mar 10;6:6471. doi: 10.1038/ncomms7471.
Despite recent advances in the cure rate of acute lymphoblastic leukaemia (ALL), the prognosis for patients with relapsed ALL remains poor. Here we identify FOXM1 as a candidate responsible for an aggressive clinical course. We show that FOXM1 levels peak at the pre-B-cell receptor checkpoint but are dispensable for normal B-cell development. Compared with normal B-cell populations, FOXM1 levels are 2- to 60-fold higher in ALL cells and are predictive of poor outcome in ALL patients. FOXM1 is negatively regulated by FOXO3A, supports cell survival, drug resistance, colony formation and proliferation in vitro, and promotes leukemogenesis in vivo. Two complementary approaches of pharmacological FOXM1 inhibition-(i) FOXM1 transcriptional inactivation using the thiazole antibiotic thiostrepton and (ii) an FOXM1 inhibiting ARF-derived peptide-recapitulate the findings of genetic FOXM1 deletion. Taken together, our data identify FOXM1 as a novel therapeutic target, and demonstrate feasibility of FOXM1 inhibition in ALL.
尽管急性淋巴细胞白血病（ALL）的治愈率最近有所提高，但复发ALL患者的预后仍然很差。在这里，我们确定FOXM1是导致侵袭性临床病程的一个候选因素。我们发现，FOXM1水平在pre-B细胞受体检查点达到峰值，但对于正常B细胞发育并非必需。与正常B细胞群体相比，ALL细胞中的FOXM1水平高2至60倍，并且可预测ALL患者的不良预后。FOXM1受FOXO3A负调控，支持细胞存活、耐药性、体外集落形成和增殖，并在体内促进白血病发生。两种互补的药理学抑制FOXM1的方法——（i）使用噻唑抗生素硫链丝菌素使FOXM1转录失活，以及（ii）一种抑制FOXM1的ARF衍生肽——重现了FOXM1基因缺失的研究结果。综上所述，我们的数据确定FOXM1为一个新的治疗靶点，并证明了在ALL中抑制FOXM1的可行性。
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