Department of Medicine V, Heidelberg University, Germany.
Institute of Applied Mathematics, Interdisciplinary Center for Scientific Computing (IWR), BIOQUANT, Heidelberg University, Germany.
Haematologica. 2017 Sep;102(9):1567-1577. doi: 10.3324/haematol.2016.163584. Epub 2017 May 26.
In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients who achieved durable remissions. However, in patients who eventually relapsed, hematopoietic stem cell numbers decreased dramatically at the time of molecular relapse demonstrating that hematopoietic stem cell levels represent an indirect marker of minimal residual disease, which heralds leukemic relapse. Upon transplantation in immune-deficient mice cases with low percentages of hematopoietic stem cells of our cohort gave rise to leukemic or no engraftment, whereas cases with normal hematopoietic stem cell levels mostly resulted in multi-lineage engraftment. Based on our experimental data, we propose that leukemic stem cells have increased niche affinity in cases with low percentages of hematopoietic stem cells. To validate this hypothesis, we developed new mathematical models describing the dynamics of healthy and leukemic cells under different regulatory scenarios. These models suggest that the mechanism leading to decreases in hematopoietic stem cell frequencies before leukemic relapse must be based on expansion of leukemic stem cells with high niche affinity and the ability to dislodge hematopoietic stem cells. Thus, our data suggest that decreasing numbers of hematopoietic stem cells indicate leukemic stem cell persistence and the emergence of leukemic relapse.
在急性髓细胞白血病患者中，低比例的醛脱氢酶阳性细胞中，可以将非白血病造血干细胞与白血病细胞分离。通过将造血干细胞频率与结果相关联，我们发现低造血干细胞频率的患者总体生存率和无病生存率均较差。对配对的诊断和随访样本的连续分析进一步表明，在获得持久缓解的患者中，化疗后造血干细胞数量增加。然而，在最终复发的患者中，造血干细胞数量在分子复发时急剧下降，表明造血干细胞水平代表微小残留疾病的间接标志物，预示着白血病复发。在免疫缺陷小鼠移植中，我们队列中低比例造血干细胞的病例导致白血病或无植入，而正常造血干细胞水平的病例大多导致多谱系植入。基于我们的实验数据，我们提出低比例造血干细胞的病例中白血病干细胞具有增加的龛位亲和力。为了验证这一假设，我们开发了新的数学模型，描述了不同调节情况下健康和白血病细胞的动力学。这些模型表明，在白血病复发之前导致造血干细胞频率下降的机制必须基于具有高龛位亲和力和驱离造血干细胞能力的白血病干细胞的扩增。因此，我们的数据表明，造血干细胞数量的减少表明白血病干细胞的持续存在和白血病复发的出现。
