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Epstein-Barr virus-negative aggressive natural killer-cell leukaemia with high P-glycoprotein activity and phosphorylated extracellular signal-regulated protein kinases 1 and 2.

Perkovic S, Basic-Kinda S, Gasparovic V, Krznaric Z, Babel J, Ilic I, Aurer I, Batinic D - Hematol Rep (2012)

Bottom Line: The patient was treated with an intensive polychemotherapy regimen designed for treatment of acute lymphoblastic leukaemia, but one month after admission developed sepsis, coma and died of cardiorespiratory arrest.We present additional evidence that, except for the immunophenotype, leukaemic NK-cells resemble normal NK-cells in terms of P-gp functional capacity and expression of phosphorylated ERK1/2 signalling molecule.In that sense drugs that block P-glycoprotein activity and activated signalling pathways might represent new means for targeted therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Diagnostics, Division of Immunology and Department of Internal Medicine;

ABSTRACT
Aggressive natural killer-cell leukaemia (ANKL) is a rare type of disease with fulminant course and poor outcome. The disease is more prevalent among Asians than in other ethnic groups and shows strong association with Epstein-Barr virus (EBV) and P-glycoprotein (P-gp) expression associated with multidrug resistance. Here we present a case of a 47 year old Caucasian female with a prior medical history of azathioprine treated ulcerative colitis who developed EBV-negative form of ANKL. The patient presented with hepatosplenomegaly, fever and nausea with peripheral blood and bone marrow infiltration with up to 70% of atypical lymphoid cells positive for cCD3, CD2, CD7, CD56, CD38, CD45, TIA1 and granzyme B, and negative for sCD3, CD4, CD5, CD8, CD34 and CD123 indicative of ANKL. Neoplastic CD56(+) NK-cells showed high level of P-glycoprotein expression and activity, but also strong expression of phosphorylated extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) MAP kinase. The patient was treated with an intensive polychemotherapy regimen designed for treatment of acute lymphoblastic leukaemia, but one month after admission developed sepsis, coma and died of cardiorespiratory arrest. We present additional evidence that, except for the immunophenotype, leukaemic NK-cells resemble normal NK-cells in terms of P-gp functional capacity and expression of phosphorylated ERK1/2 signalling molecule. In that sense drugs that block P-glycoprotein activity and activated signalling pathways might represent new means for targeted therapy.

No MeSH data available.


Related in: MedlinePlus

Analysis of NK-leukaemic cells. A) Gating of bone marrow CD56+ leukaemic cells for phenotypic and functional analysis; B) Antibody staining of phosphorylated ERK1/2 (solid line) in relation to isotypic control (dashed line); C) P-gp activity assessed by Rhodamine 123 efflux test: Rho123 efflux (dashed line) in relation to Rho123+ inhibitor (verapamil) (solid line); and D) P-gp expression by Mrk16 antibody staining (solid line) in relation to isotypic control (dashed line). Explanation in the text.
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Figure 2: Analysis of NK-leukaemic cells. A) Gating of bone marrow CD56+ leukaemic cells for phenotypic and functional analysis; B) Antibody staining of phosphorylated ERK1/2 (solid line) in relation to isotypic control (dashed line); C) P-gp activity assessed by Rhodamine 123 efflux test: Rho123 efflux (dashed line) in relation to Rho123+ inhibitor (verapamil) (solid line); and D) P-gp expression by Mrk16 antibody staining (solid line) in relation to isotypic control (dashed line). Explanation in the text.

Mentions: Further analysis concentrated on P-gp and phosphorylated signalling molecules in CD56+ neoplastic cells (Figure 2). P-gp activity was assessed using Rhodamine 123 and verapamil as an inhibitor. This functional test demonstrated high P-gp transport activity (ratio of fluorescence intensity, RFI=16.54) which was in concordance with high membrane P-gp expression (D=0.63, Kolmogorov-Smirnov test) by Mrk16 antibody staining (Kamiya Biomedical Company). Monoclonal antibody staining of cytoplasmic phosphorylated molecules Akt, ERK1/2 and p38 revealed strong phosphorylated ERK1/2 expression only (D=0.62, Kolmogorov-Smirnov test).


Epstein-Barr virus-negative aggressive natural killer-cell leukaemia with high P-glycoprotein activity and phosphorylated extracellular signal-regulated protein kinases 1 and 2.

Perkovic S, Basic-Kinda S, Gasparovic V, Krznaric Z, Babel J, Ilic I, Aurer I, Batinic D - Hematol Rep (2012)

Analysis of NK-leukaemic cells. A) Gating of bone marrow CD56+ leukaemic cells for phenotypic and functional analysis; B) Antibody staining of phosphorylated ERK1/2 (solid line) in relation to isotypic control (dashed line); C) P-gp activity assessed by Rhodamine 123 efflux test: Rho123 efflux (dashed line) in relation to Rho123+ inhibitor (verapamil) (solid line); and D) P-gp expression by Mrk16 antibody staining (solid line) in relation to isotypic control (dashed line). Explanation in the text.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3475938&req=5

Figure 2: Analysis of NK-leukaemic cells. A) Gating of bone marrow CD56+ leukaemic cells for phenotypic and functional analysis; B) Antibody staining of phosphorylated ERK1/2 (solid line) in relation to isotypic control (dashed line); C) P-gp activity assessed by Rhodamine 123 efflux test: Rho123 efflux (dashed line) in relation to Rho123+ inhibitor (verapamil) (solid line); and D) P-gp expression by Mrk16 antibody staining (solid line) in relation to isotypic control (dashed line). Explanation in the text.
Mentions: Further analysis concentrated on P-gp and phosphorylated signalling molecules in CD56+ neoplastic cells (Figure 2). P-gp activity was assessed using Rhodamine 123 and verapamil as an inhibitor. This functional test demonstrated high P-gp transport activity (ratio of fluorescence intensity, RFI=16.54) which was in concordance with high membrane P-gp expression (D=0.63, Kolmogorov-Smirnov test) by Mrk16 antibody staining (Kamiya Biomedical Company). Monoclonal antibody staining of cytoplasmic phosphorylated molecules Akt, ERK1/2 and p38 revealed strong phosphorylated ERK1/2 expression only (D=0.62, Kolmogorov-Smirnov test).

Bottom Line: The patient was treated with an intensive polychemotherapy regimen designed for treatment of acute lymphoblastic leukaemia, but one month after admission developed sepsis, coma and died of cardiorespiratory arrest.We present additional evidence that, except for the immunophenotype, leukaemic NK-cells resemble normal NK-cells in terms of P-gp functional capacity and expression of phosphorylated ERK1/2 signalling molecule.In that sense drugs that block P-glycoprotein activity and activated signalling pathways might represent new means for targeted therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Diagnostics, Division of Immunology and Department of Internal Medicine;

ABSTRACT
Aggressive natural killer-cell leukaemia (ANKL) is a rare type of disease with fulminant course and poor outcome. The disease is more prevalent among Asians than in other ethnic groups and shows strong association with Epstein-Barr virus (EBV) and P-glycoprotein (P-gp) expression associated with multidrug resistance. Here we present a case of a 47 year old Caucasian female with a prior medical history of azathioprine treated ulcerative colitis who developed EBV-negative form of ANKL. The patient presented with hepatosplenomegaly, fever and nausea with peripheral blood and bone marrow infiltration with up to 70% of atypical lymphoid cells positive for cCD3, CD2, CD7, CD56, CD38, CD45, TIA1 and granzyme B, and negative for sCD3, CD4, CD5, CD8, CD34 and CD123 indicative of ANKL. Neoplastic CD56(+) NK-cells showed high level of P-glycoprotein expression and activity, but also strong expression of phosphorylated extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) MAP kinase. The patient was treated with an intensive polychemotherapy regimen designed for treatment of acute lymphoblastic leukaemia, but one month after admission developed sepsis, coma and died of cardiorespiratory arrest. We present additional evidence that, except for the immunophenotype, leukaemic NK-cells resemble normal NK-cells in terms of P-gp functional capacity and expression of phosphorylated ERK1/2 signalling molecule. In that sense drugs that block P-glycoprotein activity and activated signalling pathways might represent new means for targeted therapy.

No MeSH data available.


Related in: MedlinePlus