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This article presents a case study of a 77-year-old female who presented with symptoms including cough, fever, confusion, and weakness. The clinician considered various diagnoses and ruled out hypothyroidism and nutritional disorders. The patient was eventually diagnosed with T-cell large granular lymphocyte (LGL) leukemia and methotrexate pneumonitis. The article highlights the importance of considering multiple diagnoses and using system-based thinking in complex cases. The authors concluded that while the patient had both LGL leukemia and methotrexate pneumonitis, methotrexate was the main driver of her symptoms. [Extracted from the article]

Chronic NK lymphoproliferative disease of large granular lymphocytes (LDGL) is characterized by the expansion of activated CD3-, CD16+ or CD56+ lymphocytes. The mechanism of survival of NK cells from LDGL patients is unknown but may be related to antigenic stimulation. There is currently no standard effective therapy for LDGL, and the disease is characteristically resistant to standard forms of chemotherapy. We found evidence of constitutive activation of extracellular-regulated kinase (ERK) in NK cells from 13/13 patients with NK-LDGL (one patient with aggressive and 12 patients with chronic disease). Ablation of ERK activity by inhibitors or a dominant-negative form of MEK, the upstream activator of ERK, reduced the survival of patient NK cells. Ras was also constitutively active in patient NK cells, and exposure of cells to the Ras inhibitor FTI2153 or to dominant-negative-Ras resulted not only in ERK inhibition but also in enhanced apoptosis in both the presence and absence of anti-Fas. Therefore, we conclude that a constitutively active Ras/MEK/ERK pathway contributes to the accumulation of NK cells in patients with NK-LDGL. These findings suggest that strategies to inhibit this signaling pathway may be useful for the treatment of the NK type of LDGL.Oncogene (2004) 23, 9220-9229. doi:10.1038/sj.onc.1208122 Published online 1 November 2004 [ABSTRACT FROM AUTHOR]