Integrated molecular profiling of juvenile myelomonocytic leukemia

Abstract

Juvenile myelomonocytic leukemia (JMML), a rare and aggressive myelodysplastic/myeloproliferative neoplasm that occurs in infants and during early childhood, is characterized by excessive myelomonocytic cell proliferation. More than 80% of patients harbor germ line and somatic mutations in RAS pathway genes (eg, <i>PTPN11</i>, <i>NF1</i>, <i>NRAS</i>, <i>KRAS</i>, and <i>CBL</i>), and previous studies have identified several biomarkers associated with poor prognosis. However, the molecular pathogenesis of 10% to 20% of patients and the relationships among these biomarkers have not been well defined. To address these issues, we performed an integrated molecular analysis of samples from 150 JMML patients. RNA-sequencing identified <i>ALK/ROS1</i> tyrosine kinase fusions (<i>DCTN1-ALK, RANBP2-ALK</i>, and <i>TBL1XR1-ROS1</i>) in 3 of 16 patients (18%) who lacked canonical RAS pathway mutations. Crizotinib, an ALK/ROS1 inhibitor, markedly suppressed <i>ALK/ROS1</i> fusion-positive JMML cell proliferation in vitro. Therefore, we administered crizotinib to a chemotherapy-resistant patient with the <i>RANBP2-ALK</i> fusion who subsequently achieved complete molecular remission. In addition, crizotinib also suppressed proliferation of JMML cells with canonical RAS pathway mutations. Genome-wide methylation analysis identified a hypermethylation profile resembling that of acute myeloid leukemia (AML), which correlated significantly with genetic markers with poor outcomes such as <i>PTPN11/NF1</i> gene mutations, 2 or more genetic mutations, an AML-type expression profile, and <i>LIN28B</i> expression. In summary, we identified recurrent activated <i>ALK/ROS1</i> fusions in JMML patients without canonical RAS pathway gene mutations and revealed the relationships among biomarkers for JMML. Crizotinib is a promising candidate drug for the treatment of JMML, particularly in patients with <i>ALK/ROS1</i> fusions.