Downes Charlotte Ej, McClure Barbara J, McDougal Daniel P, Heatley Susan L, Bruning John B, Thomas Daniel, Yeung David T, White Deborah L
Blood Cancer Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
School of Biological Sciences, Faculty of Sciences, University of Adelaide, Adelaide, SA, Australia.
Front Cell Dev Biol. 2022 Jul 12;10:942053. doi: 10.3389/fcell.2022.942053. eCollection 2022.
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from immature lymphocytes that show uncontrolled proliferation and arrested differentiation. Genomic alterations affecting Janus kinase 2 () correlate with some of the poorest outcomes within the Philadelphia-like subtype of ALL. Given the success of kinase inhibitors in the treatment of chronic myeloid leukemia, the discovery of activating point mutations and fusion genes in ALL, was a breakthrough for potential targeted therapies. However, the molecular mechanisms by which these alterations activate JAK2 and promote downstream signaling is poorly understood. Furthermore, as clinical data regarding the limitations of approved JAK inhibitors in myeloproliferative disorders matures, there is a growing awareness of the need for alternative precision medicine approaches for specific lesions. This review focuses on the molecular mechanisms behind ALL-associated mutations and fusion genes, known and potential causes of JAK-inhibitor resistance, and how alterations could be targeted using alternative and novel rationally designed therapies to guide precision medicine approaches for these high-risk subtypes of ALL.
急性淋巴细胞白血病（ALL）是最常见的儿童癌症，由未成熟淋巴细胞引发，这些细胞表现出不受控制的增殖和分化停滞。影响Janus激酶2（JAK2）的基因组改变与费城样ALL亚型中一些最差的预后相关。鉴于激酶抑制剂在治疗慢性髓性白血病方面的成功，在ALL中发现激活JAK2的点突变和融合基因，是潜在靶向治疗的一个突破。然而，这些改变激活JAK2并促进下游信号传导的分子机制尚不清楚。此外，随着关于已批准的JAK抑制剂在骨髓增殖性疾病中的局限性的临床数据逐渐成熟，人们越来越意识到需要针对特定JAK2病变采取替代的精准医学方法。本综述重点关注ALL相关JAK2突变和融合基因背后的分子机制、JAK抑制剂耐药的已知和潜在原因，以及如何使用替代的和新的合理设计疗法来靶向JAK2改变，以指导针对这些高危ALL亚型的精准医学方法。
