Advertisement

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

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. an den Heuvel-Eibrink, Jan Philippé, Nadine Van Roy, Yves Benoit, Frank Speleman, Charlotte Niemeyer, Christian Flotho, Giuseppe Basso, Geertruy te Kronnie, Pieter Van Vlierberghe and Barbara De Moerloose

Key points

  • <italic>LIN28B</italic> is overexpressed in about half of juvenile myelomonocytic leukemia patients and defines a novel fetal-like disease subgroup.

  • <italic>LIN28B</italic> expression is correlated with high fetal hemoglobin levels and the absence of monosomy 7.

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 a quarter of JMML patients present with monosomy 7 (-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 of 50 - 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. Interestingly, LIN28B overexpression was significantly correlated with higher HbF levels while patients with -7 seldom showed enhanced LIN28B expression. This gives a biological explanation of why patients with -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. Finally, high LIN28B expression was associated with poor clinical outcome in our JMML patient series, but 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.

  • Submitted September 10, 2015.
  • Accepted December 22, 2015.