Rag2null/γcnull mice are suitable for long-term in vivo propagation of juvenile myelomonocytic leukemia

CF Krombholz; K Aumann; D Bertele; A Meier; CM Niemeyer; C Flotho; M Erlacher

doi:10.1055/s-0034-1374827

Klinische Pädiatrie, Table of Contents

Rag2null/γcnull mice are suitable for long-term in vivo propagation of juvenile myelomonocytic leukemia

CF Krombholz ¹^,², K Aumann ³, D Bertele ¹, A Meier ¹, CM Niemeyer ¹, C Flotho ¹, M Erlacher ¹

¹Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Germany
²Faculty of Biology, University of Freiburg, Germany
³Department of Pathology, Institute of Clinical Pathology, University of Freiburg, Germany

Abstract

Resistance to therapy in juvenile myelomonocytic leukemia (JMML) is to a large extent determined by epigenetic modifications. For better insight into epigenetic processes in JMML-initiating cells we established a xenotransplantation model of primary human JMML cells in Rag2^null/γc^null mice.

Persistent engraftment of cells from three patients with different PTPN11 leukemia mutations was achieved by intrahepatic injection of 10⁶ cells into newborn mice or intravenous injection of 5 × 10⁶ cells into adult mice. Median infiltration with human CD45+ cells in peripheral blood, bone marrow, spleen and liver was 1%, 27%, 7% and 39%, respectively. Median time to death was 14 weeks. Many characteristics of JMML were reproduced in engrafted mice, including splenomegaly, lung infiltration, cachexia, myelomonocytic differentiation and predominance of immature leukemic progenitors in hematopoietic organs.

Absence of lymphoma or diabetes, independence of exogenous cytokines, low donor cell number and slowly progressing leukemia are advantages of the model, which is currently being used to assess the stability of epigenetic signatures in JMML and response to therapy with epigenetic modifier agents.