LIN28B overexpression defines a novel fetal-like subgroup of juvenile myelomonocytic leukemia.

Abstract

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.

• Authors: Hetty H Helsmoortel, Silvia Bresolin, Tim Lammens, Hélène Cavé, Peter Noellke, Aurélie Caye, Farzaneh Ghazavi, Andrica de Vries, Henrik Hasle, Veerle Labarque, Riccardo Masetti, Jan Stary, Marry M van den Heuvel-Eibrink, Jan Philippé, Nadine Van Roy, Yves Benoit, Frank Speleman, Charlotte Niemeyer, Christian Flotho, Giuseppe Basso, Geertruy Te Kronnie, Pieter Van Vlierberghe, Barbara De Moerloose
• Journal: Blood (Blood) Vol. 127 Issue 9 Pg. 1163-72 (Mar 03 2016) ISSN: 1528-0020 [Electronic] United States
• PMID: 26712910 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by The American Society of Hematology.

Chemical References

• Biomarkers, Tumor
• LIN28B protein, human
• RNA-Binding Proteins
• Fetal Hemoglobin

Topics

• Biomarkers, Tumor (metabolism)
• Child
• Child, Preschool
• Chromosome Deletion
• Chromosomes, Human, Pair 7 (genetics)
• Disease-Free Survival
• Female
• Fetal Hemoglobin (metabolism)
• Fetus (metabolism)
• Gene Expression Regulation, Leukemic
• Hematopoietic Stem Cell Transplantation
• Humans
• Leukemia, Myelomonocytic, Juvenile (genetics)
• Male
• Multivariate Analysis
• Prognosis
• RNA-Binding Proteins (genetics, metabolism)