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Blood. 2016 Mar 3;127(9):1163-72. doi: 10.1182/blood-2015-09-667808. Epub 2015 Dec 28.

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

Author information

1
Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium; Center for Medical Genetics, Ghent University, Ghent, Belgium;
2
Department of Women and Child Health, University of Padova, Padua, Italy;
3
Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium;
4
Department of Genetics, University Hospital of Robert Debré and Paris-Diderot University, Paris, France;
5
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany;
6
Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands;
7
Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark;
8
Pediatric Hemato-Oncology, University Hospitals Leuven, Leuven, Belgium;
9
Pediatric Hematology and Oncology, University of Bologna, Bologna, Italy;
10
Department of Pediatric Hematology/Oncology, Charles University and University Hospital Motol, Prague, Czech Republic;
11
Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands; Dutch Childhood Oncology Group, The Hague, The Netherlands; and.
12
Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University Hospital, Ghent, Belgium.
13
Center for Medical Genetics, Ghent University, Ghent, Belgium;

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.

PMID:
26712910
DOI:
10.1182/blood-2015-09-667808
[Indexed for MEDLINE]
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