Recipient sex and donor leukemic cell characteristics determine leukemogenesis in patient-derived models
Anna MP. Stanger,
Marlon Arnone,
Pauline Hanns,
Lucca M. Kimmich,
Jessica Kübler,
Sarah Gekeler,
Elsa S. Görsch,
Lea Kramer,
Marcelle Baer,
Jan C. Schroeder,
Taylor S. Mills,
Martina Konantz,
Saskia S. Rudat,
Claudia Lengerke
Affiliations
Anna MP. Stanger
University Clinic Tübingen, Department for Internal Medicine II, University of Tübingen, Tübingen
Marlon Arnone
University Clinic Tübingen, Department for Internal Medicine II, University of Tübingen, Tübingen
Pauline Hanns
University of Basel and University Hospital Basel, Department Biomedicine, Basel
Lucca M. Kimmich
University Clinic Tübingen, Department for Internal Medicine II, University of Tübingen, Tübingen
Jessica Kübler
University Clinic Tübingen, Department for Internal Medicine II, University of Tübingen, Tübingen
Sarah Gekeler
University Clinic Tübingen, Department for Internal Medicine II, University of Tübingen, Tübingen
Elsa S. Görsch
University Clinic Tübingen, Department for Internal Medicine II, University of Tübingen, Tübingen
Lea Kramer
University Clinic Tübingen, Department for Internal Medicine II, University of Tübingen, Tübingen
Marcelle Baer
University of Basel and University Hospital Basel, Department Biomedicine, Basel
Jan C. Schroeder
University Clinic Tübingen, Department for Internal Medicine II, University of Tübingen, Tübingen
Taylor S. Mills
University Clinic Tübingen, Department for Internal Medicine II, University of Tübingen, Tübingen
Martina Konantz
University of Basel and University Hospital Basel, Department Biomedicine, Basel
Saskia S. Rudat
University Clinic Tübingen, Department for Internal Medicine II, University of Tübingen, Tübingen, Germany; German Cancer Consortium (DKTK), partner site Tübingen, a partnership between DKFZ and University Hospital Tübingen
Claudia Lengerke
University Clinic Tübingen, Department for Internal Medicine II, University of Tübingen, Tübingen, Germany; German Cancer Consortium (DKTK), partner site Tübingen, a partnership between DKFZ and University Hospital Tübingen
In acute myeloid leukemia (AML), leukemogenesis depends on cell-intrinsic genetic aberrations and thus, studies on AML require investigations in an in vivo setting as provided by patient derived xenografts (PDX) models. Here we report that, next to leukemic cell characteristics, recipient sex highly influences the outgrowth of AML cells in PDX models, with females being much better repopulated than males in primary as well as secondary transplantation assays. Testosterone may be the more important player since, strikingly, better engraftment was seen in castrated versus control male recipients, while ovariectomy did not significantly impair engraftment in females. Shorter time-to-engraftment and mouse survival were observed with adverse molecular risk, and respectively with high FLT3-ITD ratio mutated AML cells. Adverse risk AML furthermore showed higher percentages of phenotypic leukemic stem cells (LSCs), suggesting impaired differentiation capacity in these AML subtypes. Overall, we achieved successful repopulation with 14/23 (61%) favorable, 18/30 (60%) intermediate and 4/8 (50%) adverse risk AML cases in female recipient PDX models. Our data identify recipient sex as an important experimental confounder in leukemia PDX models, and the contribution of the sex hormones to leukemogenesis as an intriguing, underexplored research area.
