interferon and dormant cells

[Guest guest]

AuthorEssers, Marieke, ISREC, School of life sciences, EPFL, Epalinges,

Switzerland (P)

hello friends

i just had a long conversation with a good friend, a leading hematologist

in Israel, .

he was very excited about this abstract from eha. this abstract was

elected as one of the best 5 abstracts from the meeting and will be presented at

a presidentail session.

the idea that interferon can get the dormant cells out and than kill them

with another agent, is a posible oppening to what we are all looking for- some

kind of cure for cml.

according to my friend, the timing of using ifn and glivec is important.

he thinks that the best posible treatment for new patients will be 3 months of

glivec alone, to reduce the number of the leukemic cells or burden. than he will

start interferon posibly in combination with imatinib, but it may work also as a

sole agent ending with imatinib to kill the dormant cells that were proliferated

by the ifn. according to him even when you stop the ifn, there are t-cells that

stay in the system and fight the cml cells.

i hope that there will be more trials going this direction. al in all this

is very encouraging.

best regards

giora

IFN-? PROMOTES PROLIFERATION OF DORMANT HSCS IN VIVO, MAKING THEM

SUSCEPTIBLE TO ELIMINATION BY CHEMOTHERAPY

Co-author(s) Offner, , ISREC, School of Life Sciences, Ecole

Polytechnique F?d?rale de Lausanne (EPFL), Epalinges, Switzerland

Blanco-Bose, , ISREC, School of Life Sciences, Ecole Polytechnique

F?d?rale de Lausanne (EPFL), Epalinges, Switzerland

Waibler, Zoe, Ehrlich Institute, Langen, Germany

Kalinke, Ulrich, Ehrlich Institute, Langen, Germany

Duchosal, Michel, Centre Hospitalier Universitaire Vaudois, Lausanne,

Switzerland

Trumpp, s, ISREC, School of Life Sciences, Ecole Polytechnique

F?d?rale de Lausanne (EPFL), Epalinges, Switzerland

Topic1. Developmental hematopoiesis and stem cells

KeywordsActivation, Hematopoietic stem cell, Interferon alpha

The life-long maintenance of blood is dependent on the activity of bone

marrow haematopoietic stem cells (HSCs), which are multipotent and display long

term self-renewal capacity. In the mature organism, stem cell activity is

retained in a reservoir of dormant HSCs, which do not significantly contribute

to the daily haematopoiesis. However, upon haematopoietic injury these cells can

be efficiently recruited into the cell cycle actively supporting the recovery of

the haematopoietic system. Up to now, the signals, which promote the exit of

HSCs out of the dormant stage, are largely unknown. Here we show that HSCs

efficiently exit G0 and enter the cell cycle in response to treatment with

interferon-alpha (IFN?) in vivo. IFN? treatment results in the phosphorylation

of STAT1 and PKB/Akt, and expression of IFN? target genes in HSCs, as well as

stem cell antigen (Sca-1) up-regulation at their surface. HSCs lacking

IFNAReceptor, STAT1 or Sca-1 do not show increased proliferation in response to

IFN? stimulation. Priming of HSCs with IFN? followed by treatments with the

anti-proliferative chemotherapeutic agent 5-FU causes lethality due to HSC

exhaustion, indicating that 5-FU resistant dormant HSCs can be sensitized to

this drug by pre-treatment with IFN? in vivo. These results demonstrate a novel

role for IFN? on activation of dormant stem cells in vivo and, since dormancy is

thought to be a typical feature of certain haematological tumour cells as well,

may help to clarify the so far unexplained clinical effects of IFN? on dormant

leukaemic stem cells.