Dido gene expression alterations are implicated in the induction of hematological myeloid neoplasms

Abstract

The myelodysplastic/myeloproliferative diseases (MDS/MPDs) are a heterogeneous group of myeloid neoplasms that share characteristics with chronic myeloproliferative diseases and myelodysplastic syndromes. The broad spectrum of clinical manifestations makes MDS/MPDs extremely difficult to diagnose and treat, with a median survival time of 1-5 years. No single gene defect has been firmly associated with MDS/MPDs, and no animal models have been developed for these diseases. The association of deletions on chromosome 20q with myeloid malignancies suggests the presence of unidentified tumor suppressor genes in this region. Here we show that the recently identified death inducer-obliterator (Dido) gene gives rise to at least 3 polypeptides (Dido1, Dido2, and Dido3) through alternative splicing, and we map the human gene to the long arm of chromosome 20. We found that targeting of murine Dido caused a transplantable disease whose symptoms and signs suggested MDS/MPDs. Furthermore, 100% of human MDS/MPD patients analyzed showed Dido expression abnormalities, which we also found in other myeloid but not lymphoid neoplasms or in healthy donors. Our findings suggest that Dido might be one of the tumor suppressor genes at chromosome 20q and that the Dido-targeted mouse may be a suitable model for studying MDS/MPD diseases and testing new approaches to their diagnosis and treatment.

Allogeneic bone marrow transplantation and donor lymphocyte infusion in a mouse model of irradiation-induced myelodysplastic/myeloproliferation syndrome (MD/MPS): evidence for a graft-versus-MD/MPS effect

“…According to the Bethesda guidelines for murine hematological malignancies, 29 these findings are consistent with a murine form of MD/MPS. The condition bears similarity to the genetically determined model described by Futterer et al 21 Some moribund animals exhibited monomorphic cellular infiltrates in the spleen, morphologically indicative of transformation to acute nonlymphoid leukemia (Figure 2h), whereas some others showed signs indicative of disseminated infection, such as the presence of dense poly-and mononuclear infiltrates in the liver (Figure 2i). …”

“…This clinicopathological entity is consistent with a murine form of MD/MPS. 21,29 Irradiation-induced mortality is not due to aplastic bone marrow failure…”

“…A limited number of genetically engineered mouse models of MDS exists, and these were developed with the objective of unraveling the molecular etiology and pathogenesis of MDS. [20][21][22][23] Here, we describe a radiation-induced model of MD/MPS in mice, which, in addition, is suitable for the study of allograft-mediated immune effects. Using this model, we were able to experimentally demonstrate that MD/MPS is susceptible to DLI in the context of MHC-mismatched alloBMT.…”

“…[16][17][18][19] Other than these case reports and small series, clinical data on graft-versus-MDS responses are limited. In addition, animal models of MDS are scarce: although genetically engineered mouse MDS models have been reported on, [20][21][22][23] their importance mainly lies in the study of the molecular basis and pathogenesis of MDS. In particular, GvM effects in MDS have so far not been studied experimentally.…”

“…24 Here, we report that high-dose TBI of these mice leads to an early onset and lethal syndrome that exhibits characteristics similar to human MD/MPS 2,25 and is consistent with a murine form of MD/MPS. 21 We studied the effects of allogeneic bone marrow transplantation (alloBMT) and DLI in this novel model of MD/MPS: to the best of our knowledge, we are the first to present direct evidence of the existence of a graft-versus-MD/ MPS effect induced by DLI after MHC-mismatched alloBMT.…”