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Integrated molecular profiling of juvenile myelomonocytic leukemia

Norihiro Murakami, Yusuke Okuno, Kenichi Yoshida, Yuichi Shiraishi, Genta Nagae, Kyogo Suzuki, Atsushi Narita, Hirotoshi Sakaguchi, Nozomu Kawashima, Xinan Wang, Yinyan Xu, Kenichi Chiba, Hiroko Tanaka, Asahito Hama, Masashi Sanada, Masafumi Ito, Masashi Hirayama, Arata Watanabe, Toshihide Ueno, Seiji Kojima, Hiroyuki Aburatani, Hiroyuki Mano, Satoru Miyano, Seishi Ogawa, Yoshiyuki Takahashi and Hideki Muramatsu

Key points

  • Targetable ALK/ROS1 tyrosine kinase fusions were detected in JMML patients without canonical RAS pathway mutations.

Abstract

Juvenile myelomonocytic leukemia (JMML), a rare and aggressive myelodysplastic/myeloproliferative neoplasm occurring in infants and early childhood, is characterized by excessive myelomonocytic cell proliferation. More than 80% of patients harbor germline and somatic mutations in RAS pathway genes (e.g., PTPN11, NF1, NRAS, KRAS, and CBL), and preceding studies have identified several biomarkers associated with poor prognosis. However, the molecular pathogenesis of 10–20% of patients as well as 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 ALK/ROS1 tyrosine kinase fusions (DCTN1-ALK, RANBP2-ALK, and TBL1XR1-ROS1) in 3 of 16 patients (18%) who lacked canonical RAS pathway mutations. Crizotinib, an ALK/ROS1 inhibitor, markedly suppressed ALK/ROS1–fusion positive JMML cell proliferation in vitro. Therefore, we administered crizotinib to a chemotherapy-resistant patient with the RANBP2-ALK 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 PTPN11/NF1 gene mutations, two or more genetic mutations, an “AML-type” expression profile, and LIN28B expression. In summary, we identified recurrent activated ALK/ROS1–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 ALK-/ROS1–fusions.

  • Submitted July 26, 2017.
  • Accepted January 3, 2018.