Akt Pathway May Determine the Proliferative Capacity of CLL Cells

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Leukemia. 2006 Oct 5; [Epub ahead of print]

The Akt signaling pathway determines the different proliferative

capacity of chronic lymphocytic leukemia B-cells from patients with

progressive and stable disease.

* Longo PG,

* ti L,

* Gobessi S,

* Petlickovski A,

* Pelosi M,

* Chiusolo P,

* Sica S,

* Leone G,

* Efremov DG.

1ICGEB Hematology Group, Monterotondo-Outstation, CNR Campus '

o Buzzati-Traverso', Rome, Italy.

Chronic lymphocytic leukemia (CLL) B-cells are hyporesponsive to

many proliferative signals that induce activation of normal

B-lymphocytes. However, a heterogeneous response has recently been

observed with immunostimulatory CpG-oligodeoxynucleotides (CpG ODN).

We now show that CpG ODN induce proliferation mainly in CLL B-cells

from patients with progressive disease and unmutated immunoglobulin

V(H) genes, whereas G(1)/S cell cycle arrest and apoptosis are induced

in leukemic B-cells from stable/V(H) mutated CLL.

Examination of early signaling events demonstrated that all CLL

B-cells respond to CpG ODN stimulation by degradation of the NF-kappaB

inhibitor IkappaB and activation of the Akt, ERK, JNK and p38 MAPK

kinases, but the magnitude and duration of the signaling response was

greater in the proliferating cases.

Pharmacological inhibition of these pathways showed that simultaneous

activation of Akt, ERK and JNK is required for cell cycle progression

and proliferation. Conversely, introduction of constitutively active

Akt in nonproliferating CLL B-cells resulted in induction of cyclin A

following CpG ODN stimulation, indicating that increased Akt

activation is sufficient to overcome the hyporesponsiveness of these

cells to proliferative signals.

Thus, the magnitude of Akt signaling may determine the distinct

responses observed in leukemic B-cells belonging to the different

prognostic subgroups.Leukemia advance online publication, 5 October

2006; doi:10.1038/sj.leu.2404417.

PMID: 17024114 [PubMed - as supplied by publisher]

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Akt Pathway May Determine the Proliferative

Capacity of CLL Cells

Leukemia. 2006 Oct 5; [Epub ahead of print]

The Akt signaling pathway determines the different proliferative

capacity of chronic lymphocytic leukemia B-cells from patients with

progressive and stable disease.

* Longo PG,

* ti L,

* Gobessi S,

* Petlickovski A,

* Pelosi M,

* Chiusolo P,

* Sica S,

* Leone G,

* Efremov DG.

1ICGEB Hematology Group, Monterotondo-Outstation, CNR Campus '

o Buzzati-Traverso', Rome, Italy.

Chronic lymphocytic leukemia (CLL) B-cells are hyporesponsive to

many proliferative signals that induce activation of normal

B-lymphocytes. However, a heterogeneous response has recently been

observed with immunostimulatory CpG-oligodeoxynucleotides (CpG ODN).

We now show that CpG ODN induce proliferation mainly in CLL B-cells

from patients with progressive disease and unmutated immunoglobulin

V(H) genes, whereas G(1)/S cell cycle arrest and apoptosis are induced

in leukemic B-cells from stable/V(H) mutated CLL.

Examination of early signaling events demonstrated that all CLL

B-cells respond to CpG ODN stimulation by degradation of the NF-kappaB

inhibitor IkappaB and activation of the Akt, ERK, JNK and p38 MAPK

kinases, but the magnitude and duration of the signaling response was

greater in the proliferating cases.

Pharmacological inhibition of these pathways showed that simultaneous

activation of Akt, ERK and JNK is required for cell cycle progression

and proliferation. Conversely, introduction of constitutively active

Akt in nonproliferating CLL B-cells resulted in induction of cyclin A

following CpG ODN stimulation, indicating that increased Akt

activation is sufficient to overcome the hyporesponsiveness of these

cells to proliferative signals.

Thus, the magnitude of Akt signaling may determine the distinct

responses observed in leukemic B-cells belonging to the different

prognostic subgroups.Leukemia advance online publication, 5 October

2006; doi:10.1038/sj.leu.2404417.

PMID: 17024114 [PubMed - as supplied by publisher]

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