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RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia.

ABSTRACT: Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.

SUBMITTER: Lipka DB

PROVIDER: S-EPMC5736667 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia.

Lipka Daniel B DB Witte Tania T Toth Reka R Yang Jing J Wiesenfarth Manuel M Nöllke Peter P Fischer Alexandra A Brocks David D Gu Zuguang Z Park Jeongbin J Strahm Brigitte B Wlodarski Marcin M Yoshimi Ayami A Claus Rainer R Lübbert Michael M Busch Hauke H Boerries Melanie M Hartmann Mark M Schönung Maximilian M Kilik Umut U Langstein Jens J Wierzbinska Justyna A JA Pabst Caroline C Garg Swati S Catalá Albert A De Moerloose Barbara B Dworzak Michael M Hasle Henrik H Locatelli Franco F Masetti Riccardo R Schmugge Markus M Smith Owen O Stary Jan J Ussowicz Marek M van den Heuvel-Eibrink Marry M MM Assenov Yassen Y Schlesner Matthias M Niemeyer Charlotte C Flotho Christian C Plass Christoph C

Nature communications 20171219 1

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized ...[more]

PMID: 29259247

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Project description:Background: Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm diagnosed in young children, characterized by somatic or germline mutations that lead to hyperactive RAS signaling. The only curative option is hematopoietic stem cell transplantation (HSCT). Recent data showing that aberrant DNA methylation plays a significant role in pathogenesis and correlates with clinical risk suggest a possible benefit of hypomethylating agents (HMA) in JMML treatment. Aim: The aim is to report the results of HMA-based therapy with 5-azacytidine (AZA) in three JMML patients treated in a single center, non-participating in EWOG-MDS study. Methods: The diagnosis and treatment response were evaluated according to international consensus criteria. AZA 75 mg/m2 intravenous (i.v.) was administered once daily on days 1-7 of each 28-day cycle. All patients were monitored for hematologic response, spleen size, and evolution of extramedullary disease. Targeted next generation sequencing (NGS) were performed after the 3rd AZA cycle and before SCT to evaluate the molecular alterations and genetic response. Results: Three patients diagnosed with JMML were treated with AZA (off-label indication) in Pediatric Department of Fundeni Clinical Institute, Bucharest, Romania between 2017 and 2019. There were two females and one male with median age 11 months, range 2-16 months. The cytogenetic analysis showed normal karyotype in all patients. Molecular analysis confirmed KRAS G13D mutation in two patients and NRAS G12D mutation in one patient. The clinical evaluation showed important splenomegaly and hepatomegaly in all 3 pts. One patient received AZA for early relapse after haploidentical HSCT and the other two patients received upfront AZA, as bridging therapy before HSCT. After HMA therapy, 2/3 patients achieved clinical partial response (cPR), 1/3 had clinical stable disease (cSD) and all had genetic stable disease (gSD) after 3 cycles and were able to receive the planned HSTC. One patient achieved clinical and genetic complete response before HSCT. During 22 cycles of AZA there were only four adverse events but only one determined dose reduction and treatment delay. Conclusion: Our data show that AZA monotherapy is safe and effective in controlling disease both in upfront and relapsed patients in order to proceed to HSCT.

Dataset Information

RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia.

Publications

RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia.

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