Chung Hoow Kok , Yazad Irani , Jade Clarson , Verity Saunders , Phuong Dang , Naranie Shanmuganathan , Susan Branford , David Yeung , Agnes S. M. Yong , Timothy P. Hughes
{"title":"CD302 predicts achievement of deep molecular response in patients with chronic myeloid leukemia treated with imatinib","authors":"Chung Hoow Kok , Yazad Irani , Jade Clarson , Verity Saunders , Phuong Dang , Naranie Shanmuganathan , Susan Branford , David Yeung , Agnes S. M. Yong , Timothy P. Hughes","doi":"10.1016/j.bneo.2024.100014","DOIUrl":null,"url":null,"abstract":"<div><h3>Abstract</h3><p>Achieving a deep molecular response (DMR) is a prerequisite for treatment-free remission in chronic myeloid leukemia (CML) and a key milestone for patients with CML. This study identified patients unlikely to achieve a 5-year DMR through differential expression of cluster of differentiation (CD) genes, and clinical variables at diagnosis. Peripheral blood samples (n = 131) from patients treated with imatinib or nilotinib underwent transcriptomic microarray profiling. The decision-tree analysis delineated 2 distinct poor-risk (PR) cohorts, distinguished by high 3-month <em>BCR</em>::<em>ABL1</em>% (PR-1), or high <em>CD302</em> expression (PR-2). The 5-years DMR achievement rate was significantly lower in both PR groups than in the good-risk (GR) group in patients treated frontline with imatinib (0% vs 27% vs 83%; <em>P</em> < .0001) or nilotinib (PR-2 vs GR, 17% vs 83%; <em>P</em> = .02). Gene-set enrichment analysis revealed reduced expression of cell cycle–related genes in PR-2, as well as increased metabolism and STAT3 pathway genes, which has previously been linked to leukemic cell persistence and resistance to tyrosine kinase inhibitors. Moreover, PR-2 had a higher frequency of CD34<sup>+</sup>CD302<sup>+</sup> and CD14<sup>+</sup>CD302<sup>+</sup> cells than GR samples. Strategies aimed at targeting STAT3 and/or metabolic pathways associated with high CD302 may provide novel therapeutic approaches that could help improve treatment outcomes and eradicate residual disease.</p></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950328024000141/pdfft?md5=203d3abae466c2edbbfccec17f07d8a0&pid=1-s2.0-S2950328024000141-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood Neoplasia","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2950328024000141","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
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Abstract
Achieving a deep molecular response (DMR) is a prerequisite for treatment-free remission in chronic myeloid leukemia (CML) and a key milestone for patients with CML. This study identified patients unlikely to achieve a 5-year DMR through differential expression of cluster of differentiation (CD) genes, and clinical variables at diagnosis. Peripheral blood samples (n = 131) from patients treated with imatinib or nilotinib underwent transcriptomic microarray profiling. The decision-tree analysis delineated 2 distinct poor-risk (PR) cohorts, distinguished by high 3-month BCR::ABL1% (PR-1), or high CD302 expression (PR-2). The 5-years DMR achievement rate was significantly lower in both PR groups than in the good-risk (GR) group in patients treated frontline with imatinib (0% vs 27% vs 83%; P < .0001) or nilotinib (PR-2 vs GR, 17% vs 83%; P = .02). Gene-set enrichment analysis revealed reduced expression of cell cycle–related genes in PR-2, as well as increased metabolism and STAT3 pathway genes, which has previously been linked to leukemic cell persistence and resistance to tyrosine kinase inhibitors. Moreover, PR-2 had a higher frequency of CD34+CD302+ and CD14+CD302+ cells than GR samples. Strategies aimed at targeting STAT3 and/or metabolic pathways associated with high CD302 may provide novel therapeutic approaches that could help improve treatment outcomes and eradicate residual disease.
摘要获得深度分子反应（DMR）是慢性粒细胞白血病（CML）无治疗缓解的先决条件，也是CML患者的一个重要里程碑。本研究通过分化簇（CD）基因的差异表达和诊断时的临床变量来确定不太可能实现5年DMR的患者。对接受伊马替尼或尼洛替尼治疗的患者的外周血样本（n = 131）进行了转录组芯片分析。决策树分析划分出了2个不同的低风险（PR）队列，分别是3个月BCR::ABL1%高表达（PR-1）或CD302高表达（PR-2）。在接受伊马替尼（0% vs 27% vs 83%; P <.0001）或尼洛替尼（PR-2 vs GR, 17% vs 83%; P = .02）一线治疗的患者中，两个PR组的5年DMR达标率均显著低于良险（GR）组。基因集富集分析显示，PR-2 中细胞周期相关基因的表达减少，代谢和 STAT3 通路基因的表达增加，而 STAT3 通路基因以前曾与白血病细胞的持久性和对酪氨酸激酶抑制剂的耐药性有关。此外，与GR样本相比，PR-2样本中CD34+CD302+和CD14+CD302+细胞的频率更高。针对STAT3和/或与高CD302相关的代谢途径的策略可能会提供新的治疗方法，有助于改善治疗效果和根除残留疾病。
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