-
[show abstract]
[hide abstract]
ABSTRACT: Despite blood or marrow transplantation (BMT) being arguably the most active modality against hematologic malignancies, relapses remain the major reason for failure. Many cancers have now been shown to harbor cells that are phenotypically and biologically similar to normal cells with self-renewal capacity; these so-called cancer stem cells (CSCs) typically constitute only a small fraction of the total tumor burden, but are hypothesized to be responsible for relapse after conventional-dose therapy. Here, we review whether CSCs may have relevance to BMT.
CSCs appear to be relatively resistant to standard anticancer therapies in vitro. The often-dramatic responses induced by chemotherapy in most hematologic malignancies are likely a consequence of their impressive activity against the bulk tumor cells. Although the clinical importance of CSCs remains unproven, new evidence suggests that the limited durability of many of these responses reflect resistant CSCs. It is possible that CSCs are also relatively resistant to both high-dose myeloablative conditioning and allogeneic graft-versus-tumor effects. Data on the ability of most hematologic CSCs to circulate even early in the natural history of a malignancy also raises concerns about contamination of autografts contributing to relapse.
Emerging data for the first time suggest CSCs may be responsible for relapse, even after BMT. However, BMT may be a particularly compelling setting to test CSC-targeting strategies because it provides the most effective clinical debulking of hematologic malignancies, and because CSC-targeting strategies may also enhance allogeneic antitumor immunity.
Current opinion in oncology 03/2012; 24(2):170-5. · 4.09 Impact Factor
-
Jonathan M Gerber,
B Douglas Smith,
Brownhilda Ngwang,
Hao Zhang,
Milada S Vala,
Laura Morsberger,
Steven Galkin,
Michael I Collector,
Brandy Perkins,
Mark J Levis,
Constance A Griffin,
Saul J Sharkis,
Michael J Borowitz,
Judith E Karp,
Richard J Jones
[show abstract]
[hide abstract]
ABSTRACT: Relapse of acute myeloid leukemia (AML) is thought to reflect the failure of current therapies to adequately target leukemia stem cells (LSCs), the rare, resistant cells presumed responsible for maintenance of the leukemia and typically enriched in the CD34(+)CD38(-) cell population. Despite the considerable research on LSCs over the past 2 decades, the clinical significance of these cells remains uncertain. However, if clinically relevant, it is expected that LSCs would be enriched in minimal residual disease and predictive of relapse. CD34(+) subpopulations from AML patients were analyzed by flow cytometry throughout treatment. Sorted cell populations were analyzed by fluorescence in situ hybridization for leukemia-specific cytogenetic abnormalities (when present) and by transplantation into immunodeficient mice to determine self-renewal capacity. Intermediate (int) levels of aldehyde dehydrogenase (ALDH) activity reliably distinguished leukemic CD34(+)CD38(-) cells capable of engrafting immunodeficient mice from residual normal hematopoietic stem cells that exhibited relatively higher ALDH activity. Minimal residual disease detected during complete remission was enriched for the CD34(+)CD38(-)ALDH(int) leukemic cells, and the presence of these cells after therapy highly correlated with subsequent clinical relapse. ALDH activity appears to distinguish normal from leukemic CD34(+)CD38(-) cells and identifies those AML cells associated with relapse.
Blood 01/2012; 119(15):3571-7. · 9.90 Impact Factor
-
Jonathan M Gerber,
Lu Qin,
Jeanne Kowalski,
B Douglas Smith,
Constance A Griffin,
Milada S Vala,
Michael I Collector,
Brandy Perkins,
Marianna Zahurak,
William Matsui,
Christopher D Gocke,
Saul J Sharkis,
Hyam I Levitsky,
Richard J Jones
[show abstract]
[hide abstract]
ABSTRACT: Although tyrosine kinase inhibitors have redefined the care of chronic myeloid leukemia (CML), these agents have not proved curative, likely due to resistance of the leukemia stem cells (LSC). While a number of potential therapeutic targets have emerged in CML, their expression in the LSC remains largely unknown. We therefore isolated subsets of CD34(+) stem/progenitor cells from normal donors and from patients with chronic phase or blast crisis CML. These cell subsets were then characterized based on ability to engraft immunodeficient mice and expression of candidate therapeutic targets. The CD34(+)CD38(-) CML cell population with high aldehyde dehydrogenase (ALDH) activity was the most enriched for immunodeficient mouse engrafting capacity. The putative targets: PROTEINASE 3, SURVIVIN, and hTERT were expressed only at relatively low levels by the CD34(+)CD38(-)ALDH(high) CML cells, similar to the normal CD34(+)CD38(-)ALDH(high) cells and less than in the total CML CD34(+) cells. In fact, the highest expression of these antigens was in normal, unfractionated CD34(+) cells. In contrast, PRAME and WT1 were more highly expressed by all CML CD34(+) subsets than their normal counterparts. Thus, ALDH activity appears to enrich for CML stem cells, which display an expression profile that is distinct from normal stem/progenitor cells and even the CML progenitors. Indeed, expression of a putative target by the total CD34(+) population in CML does not guarantee expression by the LSC. These expression patterns suggest that PROTEINASE 3, SURVIVIN, and hTERT are not optimal therapeutic targets in CML stem cells; whereas PRAME and WT1 seem promising.
American Journal of Hematology 01/2011; 86(1):31-7. · 4.67 Impact Factor
-
Richard J Jones,
Christopher D Gocke,
Yvette L Kasamon,
Carole B Miller,
Brandy Perkins,
James P Barber,
Milada S Vala, Jonathan M Gerber,
Lan L Gellert,
Mark Siedner,
M Victor Lemas,
Sarah Brennan,
Richard F Ambinder,
William Matsui
[show abstract]
[hide abstract]
ABSTRACT: Although Hodgkin and Reed-Sternberg (HRS) cells are B lymphoid cells, they are unlike any normal cells of that lineage. Moreover, the limited proliferative potential of HRS cells belies the clinical aggressiveness of Hodgkin lymphoma (HL). More than 20 years ago, the L428 HL cell line was reported to contain a small population of phenotypic B cells that appeared responsible for the continued generation of HRS cells. This observation, however, has never been corroborated, and such clonotypic B cells have never been documented in HL patients. We found that both the L428 and KM-H2 HL cell lines contained rare B-cell subpopulations responsible for the generation and maintenance of the predominant HRS cell population. The B cells within the HL cell lines expressed immunoglobulin light chain, the memory B-cell antigen CD27, and the stem cell marker aldehyde dehydrogenase (ALDH). Clonal CD27(+)ALDH(high) B cells, sharing immunoglobulin gene rearrangements with lymph node HRS cells, were also detected in the blood of most newly diagnosed HL patients regardless of stage. Although the clinical significance of circulating clonotypic B cells in HL remains unclear, these data suggest they may be the initiating cells for HL.
Blood 03/2009; 113(23):5920-6. · 9.90 Impact Factor
