Rampal Raajit, Ahn Jihae, Abdel-Wahab Omar, Nahas Michelle, Wang Kai, Lipson Doron, Otto Geoff A, Yelensky Roman, Hricik Todd, McKenney Anna Sophia, Chiosis Gabriela, Chung Young Rock, Pandey Suveg, van den Brink Marcel R M, Armstrong Scott A, Dogan Ahmet, Intlekofer Andrew, Manshouri Taghi, Park Christopher Y, Verstovsek Srdan, Rapaport Franck, Stephens Philip J, Miller Vincent A, Levine Ross L
Human Oncology and Pathogenesis Program, Leukemia Service.
Human Oncology and Pathogenesis Program.
Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5401-10. doi: 10.1073/pnas.1407792111. Epub 2014 Dec 2.
Patients with myeloproliferative neoplasms (MPNs) are at significant, cumulative risk of leukemic transformation to acute myeloid leukemia (AML), which is associated with adverse clinical outcome and resistance to standard AML therapies. We performed genomic profiling of post-MPN AML samples; these studies demonstrate somatic tumor protein 53 (TP53) mutations are common in JAK2V617F-mutant, post-MPN AML but not in chronic-phase MPN and lead to clonal dominance of JAK2V617F/TP53-mutant leukemic cells. Consistent with these data, expression of JAK2V617F combined with Tp53 loss led to fully penetrant AML in vivo. JAK2V617F-mutant, Tp53-deficient AML was characterized by an expanded megakaryocyte erythroid progenitor population that was able to propagate the disease in secondary recipients. In vitro studies revealed that post-MPN AML cells were sensitive to decitabine, the JAK1/2 inhibitor ruxolitinib, or the heat shock protein 90 inhibitor 8-(6-iodobenzo[d][1.3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purine-6-amine (PU-H71). Treatment with ruxolitinib or PU-H71 improved survival of mice engrafted with JAK2V617F-mutant, Tp53-deficient AML, demonstrating therapeutic efficacy for these targeted therapies and providing a rationale for testing these therapies in post-MPN AML.
骨髓增殖性肿瘤（MPN）患者发生白血病转化为急性髓系白血病（AML）的累积风险很高，这与不良临床结局及对标准AML治疗的耐药性相关。我们对MPN后AML样本进行了基因组分析；这些研究表明，体细胞肿瘤蛋白53（TP53）突变在JAK2V617F突变的MPN后AML中很常见，但在慢性期MPN中不常见，并且会导致JAK2V617F/TP53突变的白血病细胞克隆性占优势。与这些数据一致，JAK2V617F的表达与Tp53缺失相结合会在体内导致完全显性的AML。JAK2V617F突变、Tp53缺陷的AML的特征是巨核细胞红系祖细胞群体扩大，该群体能够在二次受体中传播疾病。体外研究表明，MPN后AML细胞对阿扎胞苷、JAK1/2抑制剂鲁索替尼或热休克蛋白90抑制剂8-（6-碘苯并[d][1.3]二氧杂环戊烯-5-基硫代）-9-（3-（异丙基氨基）丙基）-9H-嘌呤-6-胺（PU-H71）敏感。用鲁索替尼或PU-H71治疗可提高移植了JAK2V617F突变、Tp53缺陷的AML的小鼠的存活率，证明了这些靶向治疗的疗效，并为在MPN后AML中测试这些治疗方法提供了理论依据。
