Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies.
Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies.
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DOI：
10.1158/1078-0432.ccr-20-4054
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发表时间：
2021-04-01
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影响因子：
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通讯作者：
Watts JM
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作者：
Tayari MM;Santos HGD;Kwon D;Bradley TJ;Thomassen A;Chen C;Dinh Y;Perez A;Zelent A;Morey L;Cimmino L;Shiekhattar R;Swords RT;Watts JM
在临床前研究中，LSD1抑制剂三羟环丙胺(TCP)联合全反式维甲酸(ATRA)诱导非APL急性髓系白血病(AML)髓系母细胞分化并损害其存活。我们进行了一项I期临床试验(NCT02273102)，以评估ATRA联合TCP治疗复发/难治性AML和骨髓发育不良(MDS)患者的安全性和活性。17例患者接受全反式维甲酸和三磷酸腺苷(3种剂量水平：每天2次10 mg、2次20 mg和2次30 mg)治疗。ATRA-TCP具有可接受的安全配置文件。最大耐受量为20 mg，2次/d。疗效最好的包括1例白血病消失，1例骨髓完全缓解，2例血液学改善，2例稳定，2例稳定。按意向处理，总有效率为23.5%，临床受益率为35.3%。患者原始细胞的基因表达谱显示，与表现出更多增殖的CD34+表型相比，有应答的患者在基线时有更多静止的CD34+细胞表型，包括MYC和RARA表达减少，基因表达丰富用于细胞生长信号。在全反式维甲酸-磷酸三钙治疗中，我们观察到有反应者有显著的维甲酸(RA)靶基因诱导，但无反应者没有。我们在AML细胞系中证实了这一点，表明ATRA-TCP通过调节关键基因集的表达协同增加了分化能力和细胞死亡，关键基因集根据患者的临床反应区分患者。这些数据表明，抑制LSD1使AML细胞对ATRA敏感，并可能恢复MDS和AML患者亚群的ATRA反应性。
In preclinical studies, the LSD1 inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-APL acute myeloid leukemia (AML). We conducted a Phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS). Seventeen patients were treated with ATRA and TCP (3 dose levels: 10 mg twice daily [BID], 20 mg BID, and 30 mg BID). ATRA-TCP had an acceptable safety profile. The maximum tolerated dose of TCP was 20 mg BID. Best responses included 1 morphologic leukemia-free state, 1 marrow complete remission with hematologic improvement, 2 stable disease with hematologic improvement, and 2 stable disease. By intention-to-treat, the overall response rate was 23.5% and clinical benefit rate 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34+ cell phenotype at baseline, including decreased MYC and RARA expression, compared to non-responders that exhibited a more proliferative CD34+ phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid (RA)-target genes in responders but not non-responders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response. These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of MDS and AML patients.