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-α, 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.

中文翻译：

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未成熟的 CML 细胞实施 BMP 自分泌循环以逃避 TKI 治疗

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病。然而，TKI 尚未治愈，因为大多数患者在骨髓中保留了白血病干细胞 (LSC) 及其祖细胞，并在停止治疗后复发。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 BMP 通路改变在 TKI 耐药患者中持续存在。与完全细胞遗传学缓解的患者相比，TKI 抗性 LSC 和祖细胞显示出高水平的 BMPR1b 表达及其细胞定位的改变。单独使用 TKI 或与干扰素-α 联合对未成熟慢性期 CML 细胞进行体外治疗，导致 BMPR1b+ 细胞优先存活。我们证明了具有耐药性的患者间充质细胞持续和增加 BMP4 的产生。患者随访显示，与诊断相比，TKI 耐药患者的 LSC 中 BMPR1b 表达和 BMP4 表达增加，而敏感患者保持不变。白血病和非白血病细胞在 TKI 耐药患者的骨髓中均表现出较高的 BMP4 水平。暴露于 BMP2/BMP4 不会改变 BCR-ABL 转录表达，但伴随着 TWIST-1 的过度表达，TWIST-1 是一种在抗性 LSC 中高度表达的转录因子。通过调节 BMP4 或 BMPR1b 表达，我们表明这些元素与 TKI 抗性有关。总之，