In most patients with chronic myeloid leukemia (CML) clonal cells can be kept under control by BCR::ABL1 tyrosine kinase inhibitors (TKI). However, overt resistance or intolerance against these TKI may occur. We identified the epigenetic reader BRD4 and its downstream-effector MYC as growth regulators and therapeutic targets in CML cells. BRD4 and MYC were found to be expressed in primary CML cells, CD34⁺/CD38⁻ leukemic stem cells (LSC), and in the CML cell lines KU812, K562, KCL22, and KCL22^T315I. The BRD4-targeting drug JQ1 was found to suppress proliferation in KU812 cells and primary leukemic cells in the majority of patients with chronic phase CML. In the blast phase of CML, JQ1 was less effective. However, the BRD4 degrader dBET6 was found to block proliferation and/or survival of primary CML cells in all patients tested, including blast phase CML and CML cells exhibiting the T315I variant of BCR::ABL1. Moreover, dBET6 was found to block MYC expression and to synergize with BCR::ABL1 TKI in inhibiting the proliferation in the JQ1-resistant cell line K562. Furthermore, BRD4 degradation was found to overcome osteoblast-induced TKI resistance of CML LSC in a co-culture system and to block interferon-gamma-induced upregulation of the checkpoint antigen PD-L1 in LSC. Finally, dBET6 was found to suppress the in vitro survival of CML LSC and their engraftment in NSG mice. Together, targeting of BRD4 and MYC through BET degradation sensitizes CML cells against BCR::ABL1 TKI and is a potent approach to overcome multiple forms of drug resistance in CML LSC.

中文翻译：

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BRD4 降解可阻断 Ph+ 慢性粒细胞白血病中 MYC 的表达和多种形式的干细胞耐药性

在大多数慢性粒细胞白血病 (CML) 患者中，克隆细胞可以通过 BCR::ABL1 酪氨酸激酶抑制剂 (TKI) 进行控制。然而，可能会出现对这些 TKI 的公开抵抗或不耐受。我们将表观遗传阅读器 BRD4 及其下游效应器 MYC 确定为 CML 细胞中的生长调节剂和治疗靶点。^{BRD4 和 MYC 被发现在原代 CML 细胞、CD34 +} /CD38 ^-白血病干细胞 (LSC) 和 CML 细胞系 KU812、K562、KCL22 和 KCL22 ^T315I中表达. BRD4 靶向药物 JQ1 被发现可抑制大多数慢性期 CML 患者的 KU812 细胞和原代白血病细胞的增殖。在CML的急变期，JQ1效果较差。然而，BRD4 降解剂 dBET6 被发现可阻断所有受试患者原代 CML 细胞的增殖和/或存活，包括母细胞期 CML 和表现出 BCR::ABL1 的 T315I 变体的 CML 细胞。此外，发现 dBET6 可阻断 MYC 表达并与 BCR::ABL1 TKI 协同抑制 JQ1 抗性细胞系 K562 的增殖。此外，发现 BRD4 降解可以克服共培养系统中 CML LSC 的成骨细胞诱导的 TKI 抗性，并阻断 LSC 中干扰素-γ 诱导的检查点抗原 PD-L1 上调。最后，发现 dBET6 可以抑制CML LSC 的体外存活及其在 NSG 小鼠中的植入。总之，通过 BET 降解靶向 BRD4 和 MYC 使 CML 细胞对 BCR::ABL1 TKI 敏感，并且是克服 CML LSC 中多种形式耐药性的有效方法。