Institute of Hematology "Lorenzo and Ariosto Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy.
Leukemia. 2019 Oct;33(10):2358-2364. doi: 10.1038/s41375-019-0562-1. Epub 2019 Aug 27.
Chronic myeloid leukemia is driven by a hybrid gene, BCR-ABL1, that codes for a leukemogenic tyrosine kinase (TK) protein of 210 KDa (p210). Resistance to TK inhibitor (TKI) therapy occurs in relatively few patients, no more than 10%, while persistence of minimal residual disease during TKI therapy occurs in the great majority of patients. Resistance is a cause of death, persistence is compatible with a fairly normal length and quality of life, but may require lifelong treatment. The causes of resistance are heterogeneous, including the development of other genomic abnormalities or the altered expression of other genes, requiring different treatments. The causes of persistence may not be the same as those of resistance. We hypothesize that the variability in breakpoint position within the Major-breakpoint cluster region (M-bcr), resulting in two different messenger RNAs that may or may not include exon 14 of BCR (e13a2 and e14a2, respectively), and, as a consequence, in two p210 proteins that differ by 25 amino acids, may be a cause of persistence. The hypothesis is based on a critical review of the relationships between the BCR-ABL1 transcript types, the response to TKIs, the outcome of treatment, and the immune response, suggesting that the e14a2 transcript is associated with more and deeper molecular responses, hence with a higher probability of achieving treatment-free remission (TFR). Investigating this putative cause of persistence may help bringing more patients into stable TFR.
慢性髓性白血病由融合基因 BCR-ABL1 驱动，该基因编码一种 210 kDa 的致白血病酪氨酸激酶（TK）蛋白（p210）。只有不到 10%的患者对 TK 抑制剂（TKI）治疗产生耐药，而在大多数患者中，TKI 治疗期间仍存在微小残留疾病。耐药是导致死亡的原因，而持续存在微小残留疾病虽然与相当正常的寿命和生活质量兼容，但可能需要终身治疗。耐药的原因是多种多样的，包括其他基因组异常的发展或其他基因的表达改变，需要不同的治疗方法。而持续存在的原因可能与耐药的原因不同。我们假设 Major-breakpoint cluster region（M-bcr）内的断点位置的可变性导致两种不同的信使 RNA，分别为 e13a2 和 e14a2，分别包含或不包含 BCR 的外显子 14（e13a2 和 e14a2），进而导致两种不同的 p210 蛋白，相差 25 个氨基酸，可能是持续存在的原因。这一假设是基于对 BCR-ABL1 转录本类型、对 TKI 的反应、治疗结果和免疫反应之间的关系进行的批判性回顾，表明 e14a2 转录本与更多和更深层次的分子反应相关，因此达到无治疗缓解（TFR）的可能性更高。研究这种持续存在的潜在原因可能有助于使更多的患者进入稳定的 TFR。
