Epstein-Barr Virus-Negative Aggressive Natural Killer-Cell Leukaemia with High P-Glycoprotein Activity and Phosphorylated Extracellular Signal-Regulated Protein Kinases 1 and 2

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.

EBV-negative aggressive NK-cell leukemia/lymphoma: a clinical and pathological study from a single institution

“…There are anecdotal case reports in the literature describing neoplastic proliferation of NK cells with aggressive clinical course but no EBV association. [2][3][4][5]19 Two small series on typical EBVpositive aggressive NK-cell leukemia/lymphoma included 2 out of 13 and 2 out of 14 EBV-negative patients. 6,7 One of the small series reported the absence of EBV had no prognostic significance as both EBV-negative patients died of aggressive disease within 1-2 months.…”

“…To the best of our knowledge, there have been 16 cases reported in the English literature, [2][3][4][5][6][7][8][9] often as single case reports or rare exceptions included in the studies of EBVpositive aggressive NK-cell leukemia/lymphoma. [2][3][4][5][6][7][8] A recent study of a series of seven cases has shown that the EBV-negative aggressive NK-cell leukemia/ lymphoma is indistinguishable clinically and pathologically from EBV-positive counterpart, 9 in contrast to some earlier reports suggesting that patients with EBV-negative aggressive NK-cell leukemia/lymphoma have a less aggressive clinical course and more favorable response to treatment. 2,5,7 Most of the studies on the pathogenesis of NK/ T-cell lymphomas were on extranodal NK/T-cell lymphoma, nasal type, or its cell line derivative, with very limited information on aggressive NK-cell leukemia/lymphoma.…”

Coexistence of systemic lupus erythematosus, tuberous sclerosis and aggressive natural killer-cell leukaemia: coincidence or correlated?

“…(treatment over 17 months, cumulative dose unknown). 13 Thus, a role of a secondary malignancy due to immunosuppressive therapy is possible, although the cumulative doses in our patient were not excessively high, suggesting this is not the only permissive factor.…”

Treating Rare Lymphoproliferative Malignancies: A Focus on Indolent Large Granular Lymphocytic Leukemia

“…NK LGLL cells derived from patients had enhanced apoptosis when treated with inhibitors of ERK or MEK [36]. Increased ERK expression has also been identified in aggressive NK leukemia [37]. Tipifarnib is a farnesyltransferase inhibitor targeting Ras family of proteins, although a Phase I/II trial in patients with LGLL was terminated due to the inability to achieve primary endpoints and toxicities [38,39].…”