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.

• MeSH
• Chromosome Deletion MeSH
• Child MeSH
• Fetal Hemoglobin metabolism   MeSH
• Leukemia, Myelomonocytic, Juvenile genetics   MeSH
• Humans MeSH
• Chromosomes, Human, Pair 7 genetics   MeSH
• Multivariate Analysis MeSH
• Biomarkers, Tumor metabolism   MeSH
• Fetus metabolism   MeSH
• Child, Preschool MeSH
• Disease-Free Survival MeSH
• Prognosis MeSH
• RNA-Binding Proteins genetics   metabolism   MeSH
• Gene Expression Regulation, Leukemic MeSH
• Hematopoietic Stem Cell Transplantation MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Fetal Hemoglobin MeSH
• LIN28B protein, human MeSH Browser
• Biomarkers, Tumor MeSH
• RNA-Binding Proteins MeSH

• Keywords
• IncRNA H19 regulation, LIN28B overexpression, pediatric leukemia,
• MeSH
• Child MeSH
• Infant MeSH
• Leukemia genetics   metabolism   pathology   MeSH
• Humans MeSH
• Adolescent MeSH
• Neoplasm Proteins biosynthesis   genetics   MeSH
• Child, Preschool MeSH
• RNA-Binding Proteins biosynthesis   genetics   MeSH
• Gene Expression Regulation, Leukemic * MeSH
• RNA, Long Noncoding genetics   metabolism   MeSH
• RNA, Neoplasm genetics   metabolism   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Letter MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• H19 long non-coding RNA MeSH Browser
• LIN28B protein, human MeSH Browser
• Neoplasm Proteins MeSH
• RNA-Binding Proteins MeSH
• RNA, Long Noncoding MeSH
• RNA, Neoplasm MeSH