Microarray transcript profiling distinguishes the transient from the acute type of megakaryoblastic leukaemia (M7) in Down's syndrome, revealing PRAME as a specific discriminating marker
Suzanne McElwaine,Claire Mulligan,Jürgen Groet,Monica Spinelli,Andrea Rinaldi,Gareth Denyer,Afua Adjeiwaa Mensah,S Cavani,C. Baldo,Franca Dagna-Bricarelli,Ian Hann,Giuseppe Basso,Finbarr E. Cotter,Dean Nizetic +13 more
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TL;DR: Transient myeloproliferative disorder is a unique, spontaneously regressing neoplasia specific to Down's syndrome, and markers discriminating TMD from AMKL‐M7 in DS have the potential as predictive, diagnostic and therapeutic targets.
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Abstract: Transient myeloproliferative disorder (TMD) is a unique, spontaneously regressing neoplasia specific to Down's syndrome (DS), affecting up to 10% of DS neonates. In 20-30% of cases, it reoccurs as progressive acute megakaryoblastic leukaemia (AMKL) at 2-4 years of age. The TMD and AMKL blasts are morphologically and immuno-phenotypically identical, and have the same acquired mutations in GATA1. We performed transcript profiling of nine TMD patients comparing them with seven AMKL patients using Affymetrix HG-U133A microarrays. Similar overall transcript profiles were observed between the two conditions, which were only separable by supervised clustering. Taqman analysis on 10 TMD and 10 AMKL RNA samples verified the expression of selected differing genes, with statistical significance (P < 0.05) by Student's t-test. The Taqman differences were also reproduced on TMD and AMKL blasts sorted by a fluorescence-activated cell sorter. Among the significant differences, CDKN2C, the effector of GATA1-mediated cell cycle arrest, was increased in AMKL but not TMD, despite the similar level of GATA1. In contrast, MYCN (neuroblastoma-derived oncogene) was expressed in TMD at a significantly greater level than in AMKL. MYCN has not previously been described in leukaemogenesis. Finally, the tumour antigen PRAME was identified as a specific marker for AMKL blasts, with no expression in TMD. This study provides markers discriminating TMD from AMKL-M7 in DS. These markers have the potential as predictive, diagnostic and therapeutic targets. In addition, the study provides further clues into the pathomechanisms discerning self-regressive from the progressive phenotype.
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Citations
GATA factor mutations in hematologic disease.
TL;DR: This review focuses on hematopoietic disorders that are associated with mutations in two prominent GATA family members, GATA1 and GATA2.
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Acute megakaryoblastic leukaemia (AMKL) and transient myeloproliferative disorder (TMD) in Down syndrome: a multi‐step model of myeloid leukaemogenesis
TL;DR: The findings from these studies suggest that mutations in the key haemopoietic regulator GATA1 (GATA binding protein 1) in DS‐AMKL and DS‐TMD may be useful in diagnosis and assessing minimal residual disease, and raise the possibility of population‐based screening strategies for DS-TMD and the development of treatment to eliminate the preleukaemic TMD clone.
Tumorigenesis in Down's syndrome: big lessons from a small chromosome
Dean Nižetić,Jürgen Groet +1 more
TL;DR: Recent reports that suggest unique and only partially understood mechanisms behind Down's syndrome's paradox, including tumour repression, anti-angiogenic effects and stem cell ageing and availability are discussed.
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A causal role for the human tumor antigen preferentially expressed antigen of melanoma in cancer.
Mirjam T. Epping,René Bernards +1 more
TL;DR: It has been shown recently that PRAME functions as a repressor of retinoic acid signaling, which is a novel insight in the context of the increasing interest in tumor antigens as targets for therapy.
The role of the cancer testis antigen PRAME in tumorigenesis and immunotherapy in human cancer
TL;DR: The modulation of PRAME might be useful for the treatment of patients with cancer and this review highlights immunotherapeutic strategies that target PRAME in human malignancies.
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