Doernbecher Children's Hospital Foundation Archives - Page 2 of 2

2017

Scholar Grant

Dr. Peter Kurre

Portland, OR

Nearly half of all children diagnosed with acute myeloid leukemia (AML) will suffer relapse after successful remission induction. Disease persists in the bone marrow (BM), and work over the past decade has shown that key cellular components of the stroma, including mesenchymal stromal (MSC), undergo a remodeling process that promotes the emergence of drug-resistant clones and eventually overt relapse. The mechanisms by which AML converts the BM niche toward relapse remain to be clarified. We recently reported that AML patient-derived MSC show differences in transcriptional and cytokine release profiles, which were associated with increased resistance to tyrosine kinase inhibitor treatment. Remarkably, some of the abnormal AML-associated MSC characteristics persisted through serial in vitro passages. We then studied the dynamic remodeling in the leukemic niche in immunodeficient mice transplanted with AML cell lines (AML xenografts), and found changes in the transcriptional activity of MSC, including the overexpression of Tet2, a critical regulator of methylation as a master process governing cell function. This observation was corroborated in our genomewide methylation studies of MSC, that identified a panel of differentially methylated gene regions in AML xenografts, but not control animals.

Here, we hypothesize that Tet2 induces differential demethylation of specific MSC targets that contribute to a dysfunctional, relapse-prone AML niche.

We will determine the key genes with AML induced methylation changes in bone marrow stroma from mice that received AML patient cells.
We will test the hypothesis that changes in methylation and MSC function are driven by AML-induced gains in the activity of the Tet2 enzyme.
We will engineer AML patient derived cells with an inducible suicide switch (Luc+iCASP9+) to study the stroma in mice following experimental remission.

Our studies are designed for biologic insight and to reveal novel translational targets, with the long term goal of improving outcomes for childhood AML.

2014

Scholar Grant

Dr. Peter Kurre

Portland, OR

Leukemia is the most common cancer for children under 14 years of age. Most children present with signs of bleeding, fatigue or infection that result from their decreased blood counts and point to the progressive loss of healthy bone marrow function as leukemia cells spread. Among children who enter remission after initial treatment of the most aggressive leukemia subtype, acute myeloid leukemia (AML), half will relapse and experience the same debilitating clinical problems. The medically complex scenario combined with the need for aggressive treatment contributes significantly to prolonged hospitalization and deaths among children with AML. The critical loss of bone marrow function, however, is not simply due to the competitive displacement of healthy hematopoietic stem cells (HSC). Instead, it is becoming increasingly clear that invading leukemia cells change the supportive bone marrow environment to cause the loss of HSC. The mechanism by which AML cells “convert” the bone marrow and erode hematopoietic function is currently unknown.
We were the first to show that AML cells secrete small vesicles (exosomes) that can enter other cells and alter their function. We also showed, more recently, that AML exosomes can suppress healthy hematopoietic cells. In this proposal, we will systematically delineate the previously unrecognized role of leukemia exosomes in converting the bone marrow toward the erosion of HSC function. We will study direct and indirect mechanisms of suppression and identify the molecular switches that account for the loss and destruction of healthy stem cells. We believe that an improved understanding of how leukemia turns the bone marrow into a hostile environment for healthy stem cells will reveal potential drug targets that prevent the clinical consequences of prolonged low blood counts. We believe this work will make a significant difference in ameliorating the treatment burden and improving survival of children undergoing treatment for AML.