Immature CML cells implement a BMP autocrine loop to escape TKI treatment
Immature CML cells implement a BMP autocrine loop to escape TKI treatment
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DOI：
10.1182/blood-2017-08-801019
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发表时间：
2017-12-28
期刊：
影响因子：
20.3
通讯作者：
Maguer-Satta, Veronique
中科院分区：
文献类型：
--
作者：
Grockowiak, Elodie;Laperrousaz, Bastien;Maguer-Satta, Veronique
BCR-ABL特异性酪氨酸激酶抑制剂（TKI）改变了慢性粒细胞白血病（CML）的结局，将危及生命的疾病转变为慢性疾病。然而，TKI尚未治愈，因为大多数患者在骨髓中保留白血病干细胞（LSC）及其祖细胞，并在治疗停止后复发。在诊断时，骨形态发生蛋白（BMP）通路的失调与LSC和祖细胞扩增有关。在这里，我们报告说，BMP通路的改变持续在TKI耐药患者。与细胞遗传学完全缓解的患者相比，TKI耐药LSC和祖细胞显示出高水平的BMPR 1b表达及其细胞定位的改变。在体外单独使用TKI或与干扰素-α联合使用治疗未成熟慢性期CML细胞，可导致BMPR 1b（+）细胞优先存活。我们证明了具有抗性的患者间充质细胞的持续和增加的BMP 4产生。患者随访显示，与诊断相比，TKI耐药患者LSC中BMPR 1b表达和BMP 4表达增加，而敏感患者则保持不变。白血病和非白血病细胞在TKI耐药患者的骨髓中均表现出更高的BMP 4水平。暴露于BMP 2/BMP 4不会改变BCR-ABL转录表达，但伴随着TWIST-1的过表达，TWIST-1是一种在耐药LSC中高度表达的转录因子。通过调节BMP 4或BMPR 1b的表达，我们发现这些元素参与了TKI耐药。总之，我们揭示了BMP改变的持续性和自分泌环的存在促进CML原始细胞的TKI抗性。
The BCR-ABL specific tyrosine kinase inhibitors (TKI) changed the outcome of chronic myeloid leukemia (CML), turning a life-threatening disease into a chronic illness. However, TKI are not yet curative, because most patients retain leukemic stem cells (LSC) and their progenitors in bone marrow and relapse following treatment cessation. At diagnosis, deregulation of the bone morphogenetic protein (BMP) pathway is involved in LSC and progenitor expansion. Here, we report that BMP pathway alterations persist in TKI-resistant patients. In comparison with patients in complete cytogenetic remission, TKI-resistant LSC and progenitors display high levels of BMPR1b expression and alterations of its cellular localization. In vitro treatment of immature chronic phase CML cells with TKI alone, or in combination with interferon-a, results in the preferential survival of BMPR1b(+) cells. We demonstrated persistent and increasing BMP4 production by patients' mesenchymal cells with resistance. Patient follow-up revealed an increase of BMPR1b expression and in BMP4 expression in LSC from TKI-resistant patients in comparison with diagnosis, while remaining unchanged in sensitive patients. Both leukemic and nonleukemic cells exhibit higher BMP4 levels in the bone marrow of TKI-resistant patients. Exposure to BMP2/BMP4 does not alter BCR-ABL transcript expression but is accompanied by the overexpression of TWIST-1, a transcription factor highly expressed in resistant LSC. By modulating BMP4 or BMPR1b expression, we show that these elements are involved in TKI resistance. In summary, we reveal that persistence of BMP alterations and existence of an autocrine loop promote CML-primitive cells' TKI resistance.