Citations

Splenic extramedullary hematopoiesis is an integral component of myelofibrosis with myeloid metaplasia (MMM) and may be classified into 3 distinct histologic patterns of infiltration by myeloid precursors: diffuse, nodular, and a predominance of immature granulocytes. These 3 histologic patterns occurred in 121 (56.8%), 75 (35.2%), and 17 (8%), respectively, of 213 patients with MMM who underwent splenectomy at a single institution. In general, karyotypic findings in splenic tissue (n = 92) were similar to those seen in the bone marrow. The histologic pattern of immature granulocyte predominance, the presence of microscopic splenic infarcts (26 patients), or the detection of an abnormal splenic karyotype (52 patients) was significantly associated with decreased postsplenectomy survival. These adverse features were also associated with characteristics of advanced disease. These observations support the bone marrow origin of the myeloid progenitor pool in the spleen of patients with MMM and suggest a prognostic value for splenic histopathology and karyotype.

Unlike other leukemia types in which the bone marrow findings are diagnostic, the bone marrow pathology of T-cell granular lymphocytic leukemia (GLL) is subtle and ill-defined. In this study, bone marrow biopsy specimens from 36 patients with T-cell GLL and from 25 control patients with cytopenias and relative or absolute increases in blood large granular lymphocytes were studied by immunohistochemistry using antibodies to the cytolytic lymphocyte antigens CD8, CD56, CD57, TIA-1, and granzyme B. The goals were to clarify the bone marrow pathology of T-cell GLL and to refine the diagnostic criteria for T-cell GLL. Most bone marrow specimens from the T-cell GLL patients contained interstitially distributed clusters of at least 8 CD8+(83%) or TIA-1+ (75%) lymphocytes or clusters of at least 6 granzyme B+ (50%) lymphocytes. Interstitial clusters of CD8+, TIA-1+, or granzyme B+ cells were present in 36%, 12%, and 0%, respectively, of the control bone marrows (all values significantly different, P < .001). An additional T-cell GLL disease-specific finding was the presence of linear arrays of intravascular CD8+, TIA-1+, or granzyme B+ lymphocytes, found in 67% of cases of T-cell GLL and in none of the 25 control samples (P < .001). Staining for CD56 and CD57 was noncontributory. These findings clarify the bone marrow histopathology of T-cell GLL and provide an additional tool by which the discrete, abnormal lymphocyte population required for a diagnosis of T-cell GLL can be identified.

Abstract The adenosine triphosphate binding-site–directed agent STI571 and the tyrphostin adaphostin are undergoing evaluation as bcr/abl kinase inhibitors. The current study compared the effects of these agents on the survival of K562 cells, bcr/abl-transduced FDC-P1 cells, and myeloid progenitors from patients with chronic myelogenous leukemia (CML) compared with healthy donors. Treatment of K562 cells with 10 μM adaphostin resulted in decreased p210bcr/ablpolypeptide levels in the first 6 hours, followed by caspase activation and accumulation of apoptotic cells in less than 12 hours. By 24 hours, 90% of the cells were apoptotic and unable to form colonies. In contrast, 20 μM STI571 caused rapid inhibition of bcr/abl autophosphorylation without p210bcr/abl degradation. Although this was followed by the inhibition of Stat5 phosphorylation and the down-regulation of Bcl-xL and Mcl-1, only 7% ± 3% and 25% ± 9% of cells were apoptotic at 16 and 24 hours, respectively. Instead, the cytotoxic effects of STI571 became more pronounced with prolonged exposure, with IC90values greater than 20 μM and 1.0 ± 0.6 μM after 24 and 48 hours, respectively. Consistent with these results, 24-hour adaphostin exposure inhibited CML granulocyte colony-forming units (CFU-G) (median IC50, 12 μM) but not normal CFU-G (median IC50, greater than 20 μM), whereas 24-hour STI571 treatment had no effect on CML or normal CFU-G. Additional experiments revealed that STI571-resistant K562 cells remained sensitive to adaphostin. Moreover, the combination of STI571 + adaphostin induced more cytotoxicity in K562 cells and in CML CFU-G than either agent alone did. Collectively, these results identify adaphostin as a mechanistically distinct CML-selective agent that retains activity in STI571-resistant cell lines.