Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive stem cell disease of early childhood. RAS activation constitutes the core component of oncogenic signaling. In addition, leukemic blasts in one-fourth of JMML patients present with monosomy 7, and more than half of patients show elevated age-adjusted fetal hemoglobin (HbF) levels. Hematopoietic stem cell transplantation is the current standard of care and results in an event-free survival rate of 50% to 60%, indicating that novel molecular-driven therapeutic options are urgently needed. Using gene expression profiling in a series of 82 patient samples, we aimed at understanding the molecular biology behind JMML and identified a previously unrecognized molecular subgroup characterized by high LIN28B expression. LIN28B overexpression was significantly correlated with higher HbF levels, whereas patients with monosomy 7 seldom showed enhanced LIN28B expression. This finding gives a biological explanation of why patients with monosomy 7 are rarely diagnosed with high age-adjusted HbF levels. In addition, this new fetal-like JMML subgroup presented with reduced levels of most members of the let-7 microRNA family and showed characteristic overexpression of genes involved in fetal hematopoiesis and stem cell self-renewal. Lastly, high LIN28B expression was associated with poor clinical outcome in our JMML patient series but was not independent from other prognostic factors such as age and age-adjusted HbF levels. In conclusion, we identified elevated LIN28B expression as a hallmark of a novel fetal-like subgroup in JMML.

Center for Medical Genetics Ghent University Ghent Belgium;

Department of Clinical Chemistry Microbiology and Immunology Ghent University Hospital Ghent Belgium

Department of Genetics University Hospital of Robert Debré and Paris Diderot University Paris France;

Department of Pediatric Hematology Oncology and Stem Cell Transplantation Ghent University Hospital Ghent Belgium;

Department of Pediatric Hematology Oncology and Stem Cell Transplantation Ghent University Hospital Ghent Belgium; Center for Medical Genetics Ghent University Ghent Belgium;

Department of Pediatric Hematology Oncology Charles University and University Hospital Motol Prague Czech Republic;

Department of Pediatric Oncology Hematology Erasmus MC Sophia Children's Hospital Rotterdam The Netherlands;

Department of Pediatrics Aarhus University Hospital Skejby Aarhus Denmark;

Department of Women and Child Health University of Padova Padua Italy;

Division of Pediatric Hematology and Oncology Department of Pediatrics and Adolescent Medicine University of Freiburg Freiburg Germany;

Pediatric Hemato Oncology University Hospitals Leuven Leuven Belgium;

Pediatric Hematology and Oncology University of Bologna Bologna Italy;

Princess Maxima Center for Pediatric Oncology Utrecht The Netherlands; Dutch Childhood Oncology Group The Hague The Netherlands; and

References provided by Crossref.org

CircRNAs Dysregulated in Juvenile Myelomonocytic Leukemia: CircMCTP1 Stands Out

The long non-coding RNA landscape in juvenile myelomonocytic leukemia

LIN28B is over-expressed in specific subtypes of pediatric leukemia and regulates lncRNA H19