By expressing EVI1 in murine bone marrow (BM), we previously described a myelodysplastic syndrome (MDS) model characterized by pancytopenia, dysmegakaryopoiesis, dyserythropoiesis, and BM failure. The mice invariably died 11-14 months after BM transplantation (BMT). Here, we show that a double point mutant EVI1-(1+6Mut), unable to bind Gata1, abrogates the onset of MDS in the mouse and re-establishes normal megakaryopoiesis, erythropoiesis, BM function, and peripheral blood profiles. These normal features were maintained in the reconstituted mice until the study was ended at 21 months after BMT. We also report that EVI1 deregulates several genes that control cell division and cell selfrenewal. In striking contrast, these genes are normalized in the presence of the EVI1 mutant. Moreover, EVI1, but not the EVI1 mutant, seemingly deregulates these cellular processes by altering miRNA expression. In particular, the silencing of miRNA-124 by DNA methylation is associated with EVI1 expression, but not that of the EVI1 mutant, and appears to play a key role in the upregulation of cell division in murine BM cells and in the hematopoietic cell line 32Dcl3. The results presented here demonstrate that EVI1 induces MDS in the mouse through two major pathways, both of which require the interaction of EVI1 with other factors: one, results from EVI1-Gata1 interaction, which deregulates erythropoiesis and leads to fatal anemia, whereas the other occurs by interaction of EVI1 with unidentified factors causing perturbation of the cell cycle and self-renewal, as a consequence of silencing miRNA-124 by EVI1 and, ultimately, ensues in BM failure.T he inappropriate activation of EVI1 in 10-15% of myelodysplastic syndrome (MDS) patients is associated with megakaryocytic and erythroid dysplasia, refractory anemia unresponsive to erythropoietin (EPO) administration and bone marrow (BM) failure (1). By expressing EVI1 in murine BM cells, we generated a mouse model of MDS. The reconstituted mice showed dysplastic erythropoiesis and megakaryopoiesis, progressive pancytopenia, severe anemia, and BM failure leading to their death at 11-14 months after BM transplantation (BMT), confirming the association between EVI1 and MDS in the mouse (2). However, in contrast to the majority of EVI1-positive MDS patients, the disease in the mice never progressed to acute myeloid leukemia (AML). We proposed that the primary causes of death in the EVI1-positive mice were severe anemia, associated with loss of response to Epo, and BM failure. Using in vitro assays, we later determined that the transcription factor Gata1, required for activation of EpoR and c-Mpl (3), was functionally impaired by inappropriate interaction with EVI1, but not by EVI1-(1+6Mut), a point mutant of EVI1 that does not recognize Gata1 (4). The study reported here had two major objectives. First, we set out to determine whether the disruption in vivo of the EVI1-Gata1 interaction alleviates MDS in the mouse. We compared two groups of EVI1-and EVI1-(1+6Mut)-positive mice and showed tha...

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We have attempted to discuss some of the issues that interest pathologists who are involved in the diagnosis of CMPD and MDS. In most cases, correlation of the clinical findings with the findings in the blood and marrow will allow the morphologist to arrive at a proper diagnosis. Nevertheless, there will continue to be cases that are difficult to classify, or in which the clinical features are out of keeping with the morphologic features. These cases are challenging and thought-provoking, and the application of newer diagnostic techniques, such as molecular genetics, may provide important insights.

We report that there is an unexpectedly high incidence of second neoplasms in patients after treatment of hairy cell leukemia (HCL) with interferon alpha 2b (IFN). In a cohort of 69 patients with HCL entered in a protocol using IFN as the primary treatment, and followed thereafter for a median of 91 months (range, 0.2 to 109 months), 13 patients (19%) developed a second neoplasm. Six neoplasms were of hematopoietic origin, whereas the remaining seven were adenocarcinomas. The expected number of second tumors in this cohort is three (based on calculations from the National Cancer Institute's SEER data), so the excess frequency (observed:expected) is 4.33. However, the excess frequency is even greater for the hematopoietic neoplasms; the expected frequency is 0.15, whereas six hematopoietic tumors occurred, for an observed:expected ratio of 40. In general, the second neoplasms have behaved aggressively, and the median survival after diagnosis of the second neoplasm was only 8.8 months. Although we cannot entirely exclude the possibility that IFN therapy has some direct oncogenic effect, we suspect that increased frequency of second tumors is related to prolonged survival of patients who are immunocompromised because of HCL and thus prone to develop second tumors. If so, the frequency of second neoplasms in patients with HCL may be even greater in the future with continued improvements in therapy.

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