CD34<sup>+</sup> cell selection is required to assess <i>HOXA9</i> expression levels in patients with myelodysplastic syndrome

Heinrichs, Stefan; Berman, Jason N.; Ortiz, Taylor M.; Kornblau, Steven M.; Neuberg, Donna; Estey, Elihu H.; Look, A. Thomas

doi:10.1111/j.1365-2141.2005.05555.x

Cited by 12 publications

(8 citation statements)

References 13 publications

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“…12 Although the NUP98-HOXD13 fusion is rare in human MDS, the NHD13 fusion induces the expression of HOXA cluster genes 13 which are commonly overexpressed in human MDS. 14,15 To study its function, the Aplan laboratory generated NHD13 ϩ Tg mice that express the NHD13 transgene under control of the Vav1 promoter. 3 We first confirmed their findings that the transgenic C57Bl6 NHD13 ϩ mice develop cytopenias after approximately 4 months.…”

Section: Resultsmentioning

confidence: 99%

Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98-HOXD13–driven mouse model

Menéndez

Schlegelberger

et al. 2012

Blood

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Section: Resultsmentioning

confidence: 99%

Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98-HOXD13–driven mouse model

Menéndez

Schlegelberger

et al. 2012

Blood

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“…Although this translocation is rare in patients with MDS, it leads to overexpression of HOXA cluster genes, especially HOXA7 and HOXA9 , which is a common finding in patients with MDS [19], [20]. Transgenic mice that express a NUP98-HOXD13 ( NHD13 ) fusion gene have previously been shown to develop a MDS that closely resembles human MDS, with ineffective hematopoiesis, peripheral blood cytopenia, morphologic dysplasia, increased apoptosis, and transformation to acute leukemia between 8 and 14 months of age [21].…”

Section: Introductionmentioning

confidence: 99%

Depletion of Cytotoxic T-Cells Does Not Protect NUP98-HOXD13 Mice from Myelodysplastic Syndrome but Reveals a Modest Tumor Immunosurveillance Effect

2012

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Myelodysplastic syndrome (MDS) and aplastic anemia (AA) patients both present with symptoms of bone marrow failure. In many AA patients, these features are thought to result from an oligoclonal expansion of cytotoxic T-cells that destroy haematopoietic stem or progenitor cells. This notion is supported by the observation that AA patients respond to immunosuppressive therapy. A fraction of MDS patients also respond well to immunosuppressive therapy suggesting a similar role for cytotoxic T-cells in the etiology of MDS, however the role of cytotoxic T-cells in MDS remains unclear. Mice that express a NUP98-HOXD13 (NHD13) transgene develop a MDS that closely mimics the human condition in terms of dysplasia, ineffective hematopoiesis, and transformation to acute myeloid leukemia (AML). We followed a cohort of NHD13 mice lacking the Rag1 protein (NHD13/Rag1KO) to determine if the absence of lymphocytes might 1) delay the onset and/or diminish the severity of the MDS, or 2) effect malignant transformation and survival of the NHD13 mice. No difference was seen in the onset or severity of MDS between the NHD13 and NHD13/Rag1KO mice. However, NHD13/Rag1KO mice had decreased survival and showed a trend toward increased incidence of transformation to AML compared to the NHD13 mice, suggesting protection from AML transformation by a modest immuno-surveillance effect. In the absence of functional Tcrb signaling in the NHD13/Rag1KO T-cell tumors, Pak7 was identified as a potential Tcrb surrogate survival signal.

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“…Both the NUP98-HOX and NUP98-nonHOX fusions have been linked to MDS. Although NUP98-HOXD13 translocations are rare in patients with MDS (7-9), NUP98-HOXD13 expression leads to overexpression of HOXA9 (10), which is frequently overexpressed in patients with MDS (11), suggesting that overexpression of abd-b HOX genes is linked to MDS. In addition, transgenic mice that express a NUP98-HOXD13 (NHD13) transgene in the hematopoietic compartment develop a MDS that recapitulates all of the features of MDS, including PB cytopenias, bone marrow (BM) dysplasia, apoptosis and transformation to acute leukemia (12).…”

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Transplantation of a myelodysplastic syndrome by a long-term repopulating hematopoietic cell

Chung¹,

Choi²,

Slape³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The myelodysplastic syndromes (MDS) comprise a group of premalignant hematologic disorders characterized by ineffective hematopoiesis, dysplasia, and transformation to acute myeloid leukemia (AML). Although it is well established that many malignancies can be transplanted, there is little evidence to demonstrate that a premalignant disease entity, such as MDS or colonic polyps, can be transplanted and subsequently undergo malignant transformation in vivo. Using mice that express a NUP98-HOXD13 (NHD13) transgene in hematopoietic tissues, we show that a MDS can be transplanted to WT recipients. Recipients of the MDS bone marrow displayed all of the critical features of MDS, including peripheral blood cytopenias, dysplasia, and transformation to AML. Even when transplanted with a 10-fold excess of WT cells, the NHD13 cells outcompeted the WT cells over a 38-week period. Limiting-dilution experiments demonstrated that the frequency of the cell that could transmit the disease was Ϸ1/6,000 -1/16,000 and that the MDS was also transferable to secondary recipients as a premalignant condition. Transformation to AML in primary transplant recipients was generally delayed (46 -49 weeks after transplant); however, 6 of 10 secondary transplant recipients developed AML. These findings demonstrate that MDS originates in a transplantable, premalignant, long-term repopulating, MDS-initiating cell.hematopoiesis ͉ HOX gene ͉ leukemia ͉ transplant ͉ NUP98

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CD34⁺ cell selection is required to assess HOXA9 expression levels in patients with myelodysplastic syndrome

Cited by 12 publications

References 13 publications

Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98-HOXD13–driven mouse model

Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98-HOXD13–driven mouse model

Depletion of Cytotoxic T-Cells Does Not Protect NUP98-HOXD13 Mice from Myelodysplastic Syndrome but Reveals a Modest Tumor Immunosurveillance Effect

Transplantation of a myelodysplastic syndrome by a long-term repopulating hematopoietic cell

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CD34+ cell selection is required to assess HOXA9 expression levels in patients with myelodysplastic syndrome

Cited by 12 publications

References 13 publications

Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98-HOXD13–driven mouse model

Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98-HOXD13–driven mouse model

Depletion of Cytotoxic T-Cells Does Not Protect NUP98-HOXD13 Mice from Myelodysplastic Syndrome but Reveals a Modest Tumor Immunosurveillance Effect

Transplantation of a myelodysplastic syndrome by a long-term repopulating hematopoietic cell

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CD34⁺ cell selection is required to assess HOXA9 expression levels in patients with myelodysplastic syndrome