JAK2 aberrations in childhood B-cell precursor acute lymphoblastic leukemia
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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
Monique L. den Boer, email: [email protected]
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
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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