AUDIO JOURNAL OF ONCOLOGY
LONDON—Hematopoietic stem cells are not displaced and depleted by malignant cells in patients with acute myeloid leukaemia but merely put to sleep, according to research from London published in PNAS Early Edition. Professor John Gribben from Barts Cancer Institute in London discusses their finding and explains how this gives new opportunities for treating AML.
August 6th, 2013.
PETER GOODWIN: “Here at Queen Mary University of London scientists have discovered that in patients with acute myeloid leukaemia malignant cells do not displace and deplete normal hematopoietic stem cells — contrary to the majority view up until now. They’ve found that normal cells are merely ‘put to sleep’ by the disease and could — in principle — be woken up!”
PROFESSOR JOHN GRIBBEN: “Patients with acute myeloid leukaemia present with low blood counts — cytopenias — the premise had always been that leukemic cells displace the normal stem cells. What this study shows in fact is that the normal stem cells are very well preserved in acute myeloid leukaemia but there is a block on differentiation.”
PETER GOODWIN: “The discovery was made by checking on residual populations of normal hematopoietic stem cells in bone marrows from immuno-deficient mice transplanted with human AML. Samples from patients were also checked for their healthy stem-cell levels. The London scientists conclude that leukemic cells block normal stem-cell differentiation, but they found that this ‘imposed hibernation’ was reversible.”
PROFESSOR JOHN GRIBBEN: “Well if there had been no stem cells there because the leukemic stem cells had replaced it there would be nothing we could do. But because the stem cells are there we should be able to stimulate them. What it tells us [is] additional information yet again about the differences between caner stem cells and the normal stem cells in the body. And everything that we identify that differentiates those two types of cells represents another step towards our goal of killing a cancer stem cells but leaving the normal stem cells intact.
AUDIO MEDICA LINK: audiomedica.com
Acute myeloid leukemia (AML) induces bone marrow (BM) failure in patients, predisposing them to life-threatening infections and bleeding. The mechanism by which AML mediates this complication is unknown but one widely accepted explanation is that AML depletes the BM of hematopoietic stem cells (HSCs) through displacement. We sought to investigate how AML affects hematopoiesis by quantifying residual normal hematopoietic subpopulations in the BM of immunodeficient mice transplanted with human AML cells with a range of genetic lesions. The numbers of normal mouse HSCs were preserved whereas normal progenitors and other downstream hematopoietic cells were reduced following transplantation of primary AMLs, findings consistent with a differentiation block at the HSC–progenitor transition, rather than displacement. Once removed from the leukemic environment, residual normal hematopoietic cells differentiated normally and outcompeted steady-state hematopoietic cells, indicating that this effect is reversible. We confirmed the clinical significance of this by ex vivo analysis of normal hematopoietic subpopulations from BM of 16 patients with AML. This analysis demonstrated that the numbers of normal CD34+CD38− stem-progenitor cells were similar in the BM of AML patients and controls, whereas normal CD34+CD38+ progenitors were reduced. Residual normal CD34+ cells from patients with AML were enriched in long-term culture, initiating cells and repopulating cells compared with controls. In conclusion the data do not support the idea that BM failure in AML is due to HSC depletion. Rather, AML inhibits production of downstream hematopoietic cells by impeding differentiation at the HSC–progenitor transition.