Department of Pediatric Hematology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Hubrecht Institute, KNAW and University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Pediatr Blood Cancer. 2019 Aug;66(8):e27785. doi: 10.1002/pbc.27785. Epub 2019 May 1.
Acute myeloid leukemia (AML) is a heterogeneous disease regarding morphology, immunophenotyping, genetic abnormalities, and clinical behavior. The overall survival rate of pediatric AML is 60% to 70%, and has not significantly improved over the past two decades. Children with Down syndrome (DS) are at risk of developing acute megakaryoblastic leukemia (AMKL), which can be preceded by a transient myeloproliferative disorder during the neonatal period. Intensification of current treatment protocols is not feasible due to already high treatment-related morbidity and mortality. Instead, more targeted therapies with less severe side effects are highly needed.
To identify potential novel therapeutic targets for myeloid disorders in children, including DS-AMKL and non-DS-AML, we performed an unbiased compound screen of 80 small molecules targeting epigenetic regulators in three pediatric AML cell lines that are representative for different subtypes of pediatric AML. Three candidate compounds were validated and further evaluated in normal myeloid precursor cells during neutrophil differentiation and in (pre-)leukemic pediatric patient cells.
Candidate drugs LMK235, NSC3852, and bromosporine were effective in all tested pediatric AML cell lines with antiproliferative, proapoptotic, and differentiation effects. Out of these three compounds, the pan-histone deacetylase inhibitor NSC3852 specifically induced growth arrest and apoptosis in pediatric AML cells, without disrupting normal neutrophil differentiation.
NSC3852 is a potential candidate drug for further preclinical testing in pediatric AML and DS-AMKL.
急性髓系白血病（AML）在形态学、免疫表型、遗传异常和临床行为方面存在异质性。儿科 AML 的总生存率为 60%至 70%，在过去二十年中并未显著提高。唐氏综合征（DS）患儿有罹患急性巨核细胞白血病（AMKL）的风险，在新生儿期可能会先出现短暂的骨髓增生异常。由于已经存在较高的治疗相关发病率和死亡率，因此不能加强目前的治疗方案。相反，需要更具针对性且副作用较轻的疗法。
为了确定包括 DS-AMKL 和非-DS-AML 在内的儿科髓系疾病的潜在新治疗靶点，我们对三种儿科 AML 细胞系进行了 80 种靶向表观遗传调节剂的无偏见化合物筛选，这些细胞系代表了不同亚型的儿科 AML。验证了三种候选化合物，并在正常髓样前体细胞的中性粒细胞分化过程中和（前）白血病患儿细胞中进一步进行了评估。
候选药物 LMK235、NSC3852 和溴磺嘧啶在所有测试的儿科 AML 细胞系中均具有抗增殖、促凋亡和分化作用。在这三种化合物中，pan-histone 去乙酰化酶抑制剂 NSC3852 特异性地诱导儿科 AML 细胞生长停滞和凋亡，而不会破坏正常中性粒细胞的分化。
NSC3852 是儿科 AML 和 DS-AMKL 进一步临床前测试的潜在候选药物。
