title: 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.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium; Center for Medical Genetics, Ghent University, Ghent, Belgium;
authors.forename: Hetty H
authors.identifier: http://orcid.org/0000-0003-3412-7301
authors.initials: HH
authors.lastname: Helsmoortel
authors.affiliation: Department of Women and Child Health, University of Padova, Padua, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Bresolin
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium;
authors.forename: Tim
authors.initials: T
authors.lastname: Lammens
authors.affiliation: Department of Genetics, University Hospital of Robert Debré and Paris-Diderot University, Paris, France;
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavé
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Noellke
authors.affiliation: Department of Genetics, University Hospital of Robert Debré and Paris-Diderot University, Paris, France;
authors.forename: Aurélie
authors.initials: A
authors.lastname: Caye
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium; Center for Medical Genetics, Ghent University, Ghent, Belgium;
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Ghazavi
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands;
authors.forename: Andrica
authors.initials: A
authors.lastname: de Vries
authors.affiliation: Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark;
authors.forename: Henrik
authors.identifier: http://orcid.org/0000-0003-3976-9231
authors.initials: H
authors.lastname: Hasle
authors.affiliation: Pediatric Hemato-Oncology, University Hospitals Leuven, Leuven, Belgium;
authors.forename: Veerle
authors.identifier: http://orcid.org/0000-0002-5052-9274
authors.initials: V
authors.lastname: Labarque
authors.affiliation: Pediatric Hematology and Oncology, University of Bologna, Bologna, Italy;
authors.forename: Riccardo
authors.identifier: http://orcid.org/0000-0002-7520-9111
authors.initials: R
authors.lastname: Masetti
authors.affiliation: Department of Pediatric Hematology/Oncology, Charles University and University Hospital Motol, Prague, Czech Republic;
authors.forename: Jan
authors.initials: J
authors.lastname: Stary
authors.affiliation: Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands; Dutch Childhood Oncology Group, The Hague, The Netherlands; and.
authors.forename: Marry M
authors.identifier: http://orcid.org/0000-0002-7760-879X
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.affiliation: Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Jan
authors.identifier: http://orcid.org/0000-0003-4857-5746
authors.initials: J
authors.lastname: Philippé
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium;
authors.forename: Nadine
authors.initials: N
authors.lastname: Van Roy
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium;
authors.forename: Yves
authors.initials: Y
authors.lastname: Benoit
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium;
authors.forename: Frank
authors.identifier: http://orcid.org/0000-0002-6628-8559
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany;
authors.forename: Charlotte
authors.initials: C
authors.lastname: Niemeyer
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Flotho
authors.affiliation: Department of Women and Child Health, University of Padova, Padua, Italy;
authors.forename: Giuseppe
authors.identifier: http://orcid.org/0000-0002-2634-9302
authors.initials: G
authors.lastname: Basso
authors.affiliation: Department of Women and Child Health, University of Padova, Padua, Italy;
authors.forename: Geertruy
authors.identifier: http://orcid.org/0000-0001-7143-4795
authors.initials: G
authors.lastname: Te Kronnie
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium;
authors.forename: Pieter
authors.identifier: http://orcid.org/0000-0001-9063-7205
authors.initials: P
authors.lastname: Van Vlierberghe
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium;
authors.forename: Barbara
authors.initials: B
authors.lastname: De Moerloose
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D005319:Fetal Hemoglobin / Q000378:metabolism; D005333:Fetus / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics*; D008297:Male; D015999:Multivariate Analysis; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C516326:LIN28B protein, human; D016601:RNA-Binding Proteins; D005319:Fetal Hemoglobin