急性髓细胞性白血病(AML)是一种致命的白血病形式,传统治疗无效,并且与化学耐药性相关的复发频繁。个性化药物筛选在确定最佳方案方面有希望,然而,原代AML细胞在培养过程中经历自发凋亡,使药物筛选结果无效。这里,我们在骨髓中重建了3D成骨生态位(3DON),以支持原代AML细胞在培养物中存活和表型维持.具体来说,将来源于健康和AML供体的骨分化间充质干细胞(MSC)的3DON与原代AML细胞共培养。AML_3DON生态位下的AML细胞显示出增强的活力,减少细胞凋亡,维持CD33+CD34-表型,与AML_3DON小生境中抗凋亡细胞因子分泌增加有关。此外,AML_3DON环境下的AML细胞对两种FDA批准的化疗药物的敏感性较低,进一步表明AML_3DON生态位的生理相似性。最有趣的是,与健康_3DON小生境共培养的AML细胞对相同的样品药物高度敏感。这项研究证明了AML细胞对白血病和健康骨髓壁ni的差异反应,表明天然癌细胞生态位在药物筛选中的影响,以及在AML患者中重新设计健康骨髓生态位作为克服化疗耐药性的化疗佐剂的潜力,分别。
Acute myeloid leukemia (AML) is a deadly form of leukemia with ineffective traditional treatment and frequent chemoresistance-associated relapse. Personalized drug screening holds promise in identifying optimal regimen, nevertheless, primary AML cells undergo spontaneous apoptosis during cultures, invalidating the drug screening results. Here, we reconstitute a 3D osteogenic niche (3DON) mimicking that in bone marrow to support primary AML cell survival and phenotype maintenance in cultures. Specifically, 3DON derived from osteogenically differentiated mesenchymal stem cells (MSC) from healthy and AML donors are co-cultured with primary AML cells. The AML cells under the AML_3DON niche showed enhanced viability, reduced apoptosis and maintained CD33+ CD34-phenotype, associating with elevated secretion of anti-apoptotic cytokines in the AML_3DON niche. Moreover, AML cells under the AML_3DON niche exhibited low sensitivity to two FDA-approved chemotherapeutic drugs, further suggesting the physiological resemblance of the AML_3DON niche. Most interestingly, AML cells co-cultured with the healthy_3DON niche are highly sensitive to the same sample drugs. This study demonstrates the differential responses of AML cells towards leukemic and healthy bone marrow niches, suggesting the impact of native cancer cell niche in drug screening, and the potential of re-engineering healthy bone marrow niche in AML patients as chemotherapeutic adjuvants overcoming chemoresistance, respectively.