Biomedical subjects

Kristin J Hope

Publications and source records attributed to Kristin J Hope.

4 recordsLinked to original sources

PubMed2006

Targeting of CD44 eradicates human acute myeloid leukemic stem cells.

The long-term survival of patients with acute myeloid leukemia (AML) is dismally poor. A permanent cure of AML requires elimination of leukemic stem cells (LSCs), the only cell type capable of initiating and maintaining the leukemic clonal hierarchy. We report a therapeutic approach using an activating monoclonal antibody directed to the adhesion molecule CD44. In vivo administration of this antibody to nonobese diabetic-severe combined immune-deficient mice transplanted with human AML markedly reduced leukemic repopulation. Absence of leukemia in serially transplanted mice demonstrated that AML LSCs are directly targeted. Mechanisms underlying this eradication included interference with transport to stem cell-supportive microenvironmental niches and alteration of AML-LSC fate, identifying CD44 as a key regulator of AML LSCs. The finding that AML LSCs require interaction with a niche to maintain their stem cell properties provides a therapeutic strategy to eliminate quiescent AML LSCs and may be applicable to other types of cancer stem cells.

ADP-ribosyl Cyclase 1↗

PubMed2004

Concepts of human leukemic development.

Two fundamental problems in cancer research are identification of the normal cell within which cancer initiates and identification of the cell type capable of sustaining the growth of the neoplastic clone. There is overwhelming evidence that virtually all cancers are clonal and represent the progeny of a single cell. What is less clear for most cancers is which cells within the tumor clone possess tumorigenic or 'cancer stem cell' (CSC) properties and are capable of maintaining tumor growth. The concept that only a subpopulation of rare CSC is responsible for maintenance of the neoplasm emerged nearly 50 years ago. Testing of this hypothesis is most advanced for the hematopoietic system due to the establishment of functional in vitro and in vivo assays for stem and progenitor cells at all stages of development. This body of work led to conclusive proof for CSC with the identification and purification of leukemic stem cells capable of repopulating NOD/SCID mice. This review will focus on the historical development of the CSC hypothesis, the mechanisms necessary to subvert normal developmental programs, and the identification of the cell in which these leukemogenic events first occur.

Acute Disease↗

PubMed2004

Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity.

Emerging evidence suggests cancer stem cells sustain neoplasms; however, little is understood of the normal cell initially targeted and the resultant cancer stem cells. We show here, by tracking individual human leukemia stem cells (LSCs) in nonobese diabetic-severe combined immunodeficiency mice serially transplanted with acute myeloid leukemia cells, that LSCs are not functionally homogeneous but, like the normal hematopoietic stem cell (HSC) compartment, comprise distinct hierarchically arranged LSC classes. Distinct LSC fates derived from heterogeneous self-renewal potential. Some LSCs emerged only in recipients of serial transplantation, indicating they divided rarely and underwent self-renewal rather than commitment after cell division within primary recipients. Heterogeneity in LSC self-renewal potential supports the hypothesis that they derive from normal HSCs. Furthermore, normal developmental processes are not completely abolished during leukemogenesis. The existence of multiple stem cell classes shows the need for LSC-targeted therapies.

Animals↗

PubMedDate not supplied

Human acute myeloid leukemia stem cells.

Acute myeloid leukemia (AML) is a clonal disorder defined by the accumulation of abnormally differentiated myeloid cells that are not mature; any myeloid lineage can be affected and the extent of maturation of the leukemia blasts can also vary. Because mature blast cells of AML have very limited proliferative capacity, it is believed that the leukemic clone is perpetuated by a rare population of leukemia stem cells (LSC) that have acquired a dramatic increase in their ability to self-renew. Elucidating the nature of the target cell that undergoes leukemic transformation and the resultant LSC that can initiate and maintain AML is essential for both the understanding of the leukemogenic process and for the design of effective therapies. However, identifying such cells using only clinical data from human subjects has been difficult due to obvious restriction in experimental intervention in humans. In addition, before clinical symptoms are presented, it is virtually impossible to acquire a complete picture of the early events in leukemogenesis. Other experimental approaches involved the study of naturally occurring or induced animal (murine) leukemias. While many aspects of these animal leukemias reproduced the human disease, there were also inconsistencies. The advent of xenotransplantation to accurately model human AML growing within an animal system has provided an important tool to begin to answer the fundamental questions regarding AML. This review will examine the work done using the xenograft system to characterize the nature of the leukemic clone and will specifically highlight the advances made in phenotypically, molecularly, and functionally defining the LSC. Finally, a variety of novel AML therapeutics aimed at eradicating the LSC will be discussed.

Animals↗