Acute lymphocytic leukemia - progenitor but not only stem cell disease.
In Journal club, leukemia, leukemic stem cell | 4 comments | permalink
I’m continuing stories about leukemic stem cells (LSC) because it’s “the billion dollar question” according Michael Clarke, and maybe a new hope for leukemia patients to live a normal life without relapses.
It was proposed by John Dick group at University of Toronto that acute myelogenous leukemia (AML) arises from a specific minor population of cells - leukemia initiating cells (LIC) in humans.
All of LIC studies are based on well done experimental xenotransplantation assay. Researchers take human leukemia samples, sort out candidates for LIC, and transplant them into the immunodeficient mice, which are not able to reject human hematopoietic cells. The LIC or cancer stem cells, the cells that make transferable disease in a serial transplant (from one mouse to another and further), have an ability to self-renew. So, Dick and collegues show that only CD34+/CD38- cells, sorted from human AML sample can transfer disease from mouse to mouse, but not other populations. It seems like it’s not the case for human lymphocytic leukemia (ALL) - the most common hematological malignancy in childhood. A new study, from Japan, published online in Leukemia journal, shows that in B-cell ALL progenitors as well as stem cells could initiate and transfer disease.
This study is complementary to recently publish work, identifying LIC for ALL. Both studies used CD34+/CD38-/CD19+ cells like an LIC. CD19 - is common B-cell marker. Authors found that both CD34+/CD38+/CD19+ (progenitor) and CD34+/CD38-/CD19+ (stem) cells initiate B-ALL. Both populations equally caused malignant diseases in primary and secondary recepients.
Other clinically important conclusion, based on their findings:
suggests that by CD34+/CD38-/CD10-/CD19- purification, the potential contamination of autologous stem cell graft by B-ALL LSCs may be avoidable.
I have to notice that japanese team used incredible tool - NOG (=NOD/SCID/IL2R-gamma-null) mice, which are considered the best human himeric xeno-model so far. I think this paper gives another example of how well the NOG mice work, and will help Jax lab make more money from these mice.
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Leukemia AOP 17 April 2008; doi: 10.1038/leu.2008.83
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Maybe all of cells capable of producing differentiated cells (e.g. stem cells as well as progenitors) can cause acute lymphocytic leukemia. Conceptually, I don’t think this is surprising provided that the disease is not chronic but acute. However, more important issue here is whether mice that were transplanted with leukemic progenitors can be completely curable by traditional methods such as irradiation, chemotherapy, fresh bone marrow transplantation, in contrast to those that were transplanted with leukemic stem cells, and if antibody-specific method against leukemic stem cells helps a complete cure for leukemia. I’m not sure whether people have directly compared these two.
I don’t think all stem-progenitor cells can cause B-ALL.
Authors demonstrated that CD34+/CD38-/CD19-/CD10- human normal HSC sorted from ALL sample showed normal human hematopoietic repopulation but not give a leukemia. Maybe downstream progenitors also are not able (they didn’t check). So there is kind of selectivity.
According therapeutic approaches, I don’t know anybody who compared traditional chemotherapy with targeting of LSC in one human model, but these guys show that traditional drug Ara-C doesn’t kill them. Another work got close to answer, but I DIDN’T FIND A SURVIVAL CURVE! (isn’t it funny?)
It is not known whether leukemic progenitors are killed by Ara-C and hence B-ALL is reversed. That’s what I meant. It will be a good experiment to demonstrate that leukemic stem cells are resistant to Ara-C and hence something different is necessary for the treatment.
yes, sure it’s will be nice experiment, nobody done in ALL model yet