1: Br J Haematol. 2004 Jun;125(6):729-42. 

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.

McElwaine S, Mulligan C, Groet J, Spinelli M, Rinaldi A, Denyer G, Mensah A,
Cavani S, Baldo C, Dagna-Bricarelli F, Hann I, Basso G, Cotter FE, Nizetic D.

Centre for Haematology, Institute of Cell and Molecular Science, Barts and The
London, Queen Mary's School of Medicine, University of London, Medical College
Building, Turner Street, London, UK.

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.

PMID: 15180862 [PubMed - indexed for MEDLINE]


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