Jacobi Henrike, Vieri Margherita, Bütow Marlena, Namasu Carolina Y, Flüter Laura, Costa Ivan G, Maié Tiago, Lindemann-Docter Katharina, Chatain Nicolas, Beier Fabian, Huber Michael, Wagner Wolfgang, Crysandt Martina, Brümmendorf Tim H, Schemionek Mirle
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany.
Front Pharmacol. 2023 Jul 4;14:1212392. doi: 10.3389/fphar.2023.1212392. eCollection 2023.
The management of patients with chronic myeloid leukemia (CML) has been revolutionized by the introduction of tyrosine kinase inhibitors (TKIs), which induce deep molecular responses so that treatment can eventually be discontinued, leading to treatment-free remission (TFR) in a subset of patients. Unfortunately, leukemic stem cells (LSCs) often persist and a fraction of these can again expand in about half of patients that attempt TKI discontinuation. In this study, we show that presence of myelofibrosis (MF) at the time of diagnosis is a factor associating with TFR failure. Fibrotic transformation is governed by the action of several cytokines, and interestingly, some of them have also been described to support LSC persistence. At the cellular level, these could be produced by both malignant cells and by components of the bone marrow (BM) niche, including megakaryocytes (MKs) and mesenchymal stromal cells (MSCs). In our cohort of 57 patients, around 40% presented with MF at diagnosis and the number of blasts in the peripheral blood and BM was significantly elevated in patients with higher grade of MF. Employing a CML transgenic mouse model, we could observe higher levels of alpha-smooth muscle actin (α-SMA) in the BM when compared to control mice. Short-term treatment with the TKI nilotinib, efficiently reduced spleen weight and mRNA levels, while α-SMA expression was only partially reduced. Interestingly, the number of MKs was increased in the spleen of CML mice and elevated in both BM and spleen upon nilotinib treatment. Analysis of human CML-vs healthy donor (HD)-derived MSCs showed an altered expression of gene signatures reflecting fibrosis as well as hematopoietic support, thus suggesting MSCs as a potential player in these two processes. Finally, in our cohort, 12 patients qualified for TKI discontinuation, and here we observed that all patients who failed TFR had BM fibrosis at diagnosis, whereas this was only the case in 25% of patients with achieved TFR, further supporting the link between fibrosis and LSC persistence.
酪氨酸激酶抑制剂（TKIs）的引入彻底改变了慢性髓性白血病（CML）患者的治疗方式，这些抑制剂可诱导深度分子反应，从而使治疗最终能够停止，在一部分患者中实现无治疗缓解（TFR）。不幸的是，白血病干细胞（LSCs）往往会持续存在，并且在尝试停用TKI的患者中，约有一半患者体内的一部分LSCs会再次增殖。在本研究中，我们表明诊断时存在骨髓纤维化（MF）是与TFR失败相关的一个因素。纤维化转变受多种细胞因子的作用支配，有趣的是，其中一些细胞因子也被描述为支持LSC的持续存在。在细胞水平上，这些细胞因子可由恶性细胞以及骨髓（BM）微环境的成分产生，包括巨核细胞（MKs）和间充质基质细胞（MSCs）。在我们的57例患者队列中，约40%的患者在诊断时出现MF，MF程度较高的患者外周血和BM中的原始细胞数量显著升高。利用CML转基因小鼠模型，与对照小鼠相比，我们可以观察到BM中α平滑肌肌动蛋白（α-SMA）水平更高。用TKI尼罗替尼进行短期治疗可有效降低脾脏重量和mRNA水平，而α-SMA表达仅部分降低。有趣的是，CML小鼠脾脏中的MK数量增加，尼罗替尼治疗后BM和脾脏中的MK数量均升高。对人CML与健康供体（HD）来源的MSCs进行分析，结果显示反映纤维化以及造血支持的基因特征表达发生改变，因此表明MSCs在这两个过程中可能发挥作用。最后，在我们的队列中，有12例患者符合停用TKI的条件，在此我们观察到，所有TFR失败的患者在诊断时都有BM纤维化，而在实现TFR的患者中只有25%是这种情况，这进一步支持了纤维化与LSC持续存在之间的联系。
