Oncotarget

Research Papers:

JAK2 aberrations in childhood B-cell precursor acute lymphoblastic leukemia

Elisabeth M.P. Steeghs, Isabel S. Jerchel, Willemieke de Goffau-Nobel, Alex Q. Hoogkamer, Judith M. Boer, Aurélie Boeree, Cesca van de Ven, Marco J. Koudijs, Nicolle J.M. Besselink, Hester A. de Groot-Kruseman, Christian Michel Zwaan, Martin A. Horstmann, Rob Pieters and Monique L. den Boer _

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Oncotarget. 2017; 8:89923-89938. https://doi.org/10.18632/oncotarget.21027

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Abstract

Elisabeth M.P. Steeghs1,*, Isabel S. Jerchel1,*, Willemieke de Goffau-Nobel1, Alex Q. Hoogkamer1, Judith M. Boer1,6, Aurélie Boeree1, Cesca van de Ven1, Marco J. Koudijs2,3, Nicolle J.M. Besselink2,3, Hester A. de Groot-Kruseman4, Christian Michel Zwaan1,4, Martin A. Horstmann5, Rob Pieters4,6 and Monique L. den Boer1,4,6

1Department of Pediatric Oncology/Hematology, Erasmus Medical Centre – Sophia Children’s Hospital, Rotterdam, The Netherlands

2Centre for Personalized Cancer Treatment, Utrecht, The Netherlands

3Department of Medical Genetics, University Medical Centre, Utrecht, The Netherlands

4DCOG, Dutch Childhood Oncology Group, The Hague, The Netherlands

5COALL - German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia, Hamburg, Germany

6Princess Máxima Centre for Pediatric Oncology, Utrecht, The Netherlands

*These authors have contributed equally to this work

Correspondence to:

Monique L. den Boer, email: m.l.denboer@erasmusmc.nl

Keywords: JAK2, B-cell precursor acute lymphoblastic leukemia, pediatric, targeted therapies, JAK inhibitors

Received: April 21, 2017     Accepted: July 31, 2017     Published: September 16, 2017

ABSTRACT

JAK2 abnormalities may serve as target for precision medicines in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In the current study we performed a screening for JAK2 mutations and translocations, analyzed the clinical outcome and studied the efficacy of two JAK inhibitors in primary BCP-ALL cells. Importantly, we identify a number of limitations of JAK inhibitor therapy.

JAK2 mutations mainly occurred in the poor prognostic subtypes BCR-ABL1-like and non- BCR-ABL1-like B-other (negative for sentinel cytogenetic lesions). JAK2 translocations were restricted to BCR-ABL1-like cases. Momelotinib and ruxolitinib were cytotoxic in both JAK2 translocated and JAK2 mutated cells, although efficacy in JAK2 mutated cells highly depended on cytokine receptor activation by TSLP. However, our data also suggest that the effect of JAK inhibition may be compromised by mutations in alternative survival pathways and microenvironment-induced resistance. Furthermore, inhibitors induced accumulation of phosphorylated JAK2Y1007, which resulted in a profound re-activation of JAK2 signaling upon release of the inhibitors. This preclinical evidence implies that further optimization and evaluation of JAK inhibitor treatment is necessary prior to its clinical integration in pediatric BCP-ALL.


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