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

(2016) BLOOD. 127(9). p.1163-1172
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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.
Keywords
MUTATIONS, PATHWAY, CLONALITY, NEUROBLASTOMA, EXPRESSION, STEM-CELLS, CHRONIC MYELOGENOUS LEUKEMIA, RETROSPECTIVE ANALYSIS, ORIGIN, CANCER

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Chicago
Helsmoortel, Hetty, Silvia Bresolin, Tim Lammens, Hélène Cavé, Peter Noellke, Aurélie Caye, Farzaneh Ghazavi, et al. 2016. “LIN28B Overexpression Defines a Novel Fetal-like Subgroup of Juvenile Myelomonocytic Leukemia.” Blood 127 (9): 1163–1172.
APA
Helsmoortel, H., Bresolin, S., Lammens, T., Cavé, H., Noellke, P., Caye, A., Ghazavi, F., et al. (2016). LIN28B overexpression defines a novel fetal-like subgroup of juvenile myelomonocytic leukemia. BLOOD, 127(9), 1163–1172.
Vancouver
1.
Helsmoortel H, Bresolin S, Lammens T, Cavé H, Noellke P, Caye A, et al. LIN28B overexpression defines a novel fetal-like subgroup of juvenile myelomonocytic leukemia. BLOOD. 2016;127(9):1163–72.
MLA
Helsmoortel, Hetty, Silvia Bresolin, Tim Lammens, et al. “LIN28B Overexpression Defines a Novel Fetal-like Subgroup of Juvenile Myelomonocytic Leukemia.” BLOOD 127.9 (2016): 1163–1172. Print.
@article{7037118,
  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.},
  author       = {Helsmoortel, Hetty and Bresolin, Silvia and Lammens, Tim and Cav{\'e}, H{\'e}l{\`e}ne and Noellke, Peter and Caye, Aur{\'e}lie and Ghazavi, Farzaneh and de Vries, Andrica and Hasle, Henrik and Labarque, Veerle and Masetti, Riccardo and Stary, Jan and van den Heuvel-Eibrink, Marry M and Philipp{\'e}, Jan and Van Roy, Nadine and Benoit, Yves and Speleman, Franki and Niemeyer, Charlotte and Flotho, Christian and Basso, Giuseppe and te Kronnie, Geertruy and Van Vlierberghe, Pieter and De Moerloose, Barbara},
  issn         = {0006-4971},
  journal      = {BLOOD},
  language     = {eng},
  number       = {9},
  pages        = {1163--1172},
  title        = {LIN28B overexpression defines a novel fetal-like subgroup of juvenile myelomonocytic leukemia},
  url          = {http://dx.doi.org/10.1182/blood-2015-09-667808},
  volume       = {127},
  year         = {2016},
}

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