Uckun Fatih M, Qazi Sanjive
Ares Pharmaceuticals, St. Paul, MN 55110, USA.
Cancer Drug Resist. 2022 Oct 9;5(4):902-916. doi: 10.20517/cdr.2022.78. eCollection 2022.
The main goal of this study was to elucidate at the transcript level the tyrosine kinase expression profiles of primary leukemia cells from mixed lineage leukemia 1 gene rearranged (KMT2A/MLL-R) acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. We evaluated protein tyrosine kinase (PTK) gene expression profiles of primary leukemic cells in KMT2A/MLL-R AML and ALL patients using publicly available archived datasets. Our studies provided unprecedented evidence that the genetic signatures of KMT2A/MLL-R AML and ALL cells are characterized by transcript-level overexpression of specific PTK. In infants, children and adults with KMT2A/MLL-R ALL, as well as pediatric patients with KMT2A/MLL-R AML, the gene expression levels for FLT3, BTK, SYK, JAK2/JAK3, as well as several SRC family PTK were differentially amplified. In adults with KMT2A/MLL-R AML, the gene expression levels for SYK, JAK family kinase TYK2, and the SRC family kinases FGR and HCK were differentially amplified. These results provide new insights regarding the clinical potential of small molecule inhibitors of these PTK, many of which are already FDA/EMA-approved for other indications, as components of innovative multi-modality treatment platforms against KMT2A/MLL-R acute leukemias.
本研究的主要目标是在转录水平阐明混合谱系白血病1基因重排（KMT2A/MLL-R）的急性髓系白血病（AML）和急性淋巴细胞白血病（ALL）患者原代白血病细胞的酪氨酸激酶表达谱。我们使用公开可用的存档数据集评估了KMT2A/MLL-R AML和ALL患者原代白血病细胞的蛋白酪氨酸激酶（PTK）基因表达谱。我们的研究提供了前所未有的证据，表明KMT2A/MLL-R AML和ALL细胞的基因特征表现为特定PTK在转录水平的过表达。在患有KMT2A/MLL-R ALL的婴儿、儿童和成人以及患有KMT2A/MLL-R AML的儿科患者中，FLT3、BTK、SYK、JAK2/JAK3以及几种SRC家族PTK的基因表达水平存在差异扩增。在患有KMT2A/MLL-R AML的成人中，SYK、JAK家族激酶TYK2以及SRC家族激酶FGR和HCK的基因表达水平存在差异扩增。这些结果为这些PTK小分子抑制剂的临床潜力提供了新的见解，其中许多已获FDA/EMA批准用于其他适应症，可作为针对KMT2A/MLL-R急性白血病的创新多模式治疗平台的组成部分。
