Christopher C. Porter, MD
The cancer stem cell (CSC) hypothesis has generated a great deal of interest for oncologists of all specialties. Yet, its origins lie in the understanding of the hierarchical organization of normal hematopoiesis and the pioneering work of hematologists like John Dick, demonstrating a recapitulation of that organization in acute myeloid leukemia (AML). This afternoon, in an oral session titled “Hematopoiesis – Malignant Stem and Progenitor Cells: Malignant Stem and Progenitor Cells,” (4:30-6:00 p.m. in Room 224 ABEF) scientists will present some of the most up-to-date data about leukemia stem cells (LSCs).
The CSC hypothesis posits that within tumors exists a population of cells with the unique ability to both self-renew and give rise to all of the heterogeneous cell types within a tumor. These cells have implications for therapy, as curative therapy necessitates their elimination. Extensive work has demonstrated that LSCs in AML are a rare population that can be studied using cell surface staining.
There will be a broad spectrum of data presented from a variety of models. For example, Dr. Eric Lechman from Dr. Dick’s group will present data demonstrating an apparent role of microRNA-126 in the maintenance of LSC activity (abstract #94), while Dr. Paresh Vyas will show the molecular characterization of two previously undescribed leukemia progenitor cell populations that they have isolated (abstract #91).
Two novel mouse models provide insight into LSC biology. Dr. Keisuke Ito will show data from adult mice in which nucleophosmin (Npm1) is conditionally knocked out, demonstrating that Npm1 ablation leads to an MDS-like disease (abstract #95). When combined with p53 disruption, Npm1 knockout results in accelerated AML development. Dr. Petra Tschanter will present work that demonstrates how a novel cell-cycle regulator, INCA1, influences leukemia maintenance (abstract #96). Mice that lack this gene have an enlarged stem cell pool with functional defects. When programmed to develop AML1-ETO+ leukemia, Inca1-deficient bone marrow cells are much less efficient at generating leukemia than wild-type cells.
In a presentation that could have immediate clinical implications, Dr. Florian Heidel will present work showing that in Bcr-Abl+ leukemia in which β-catenin expression is eliminated, survival is only modestly improved, but leukemia burden in the bone marrow is substantially reduced (abstract #93). Treatment of mice with imatinib reduces the numbers of an LSC-enriched population, more so in those with β-catenin-negative leukemia. When given with imatinib, indomethacin, a β-catenin inhibitor, reduces an LSC-enriched population more than imatinib alone and diminishes the capacity of the leukemia to engraft tertiary recipients.
Highlighting the need for caution when considering the CSC hypothesis for diseases other than AML, Dr. Klaus Rehe will show how his team addressed the frequency of LSC in acute lymphoblastic leukemia (ALL) and demonstrate that the frequency of LSC in phenotypically different populations are similar and quite high in their model, thus exhibiting another biologic difference between ALL and AML.
The data presented comes from laboratories of the highest caliber from around the world. The session will be informative for all attendees, but expect the answers presented to raise even more questions.
Dr. Porter indicated no relevant conflicts of interest.