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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1558-1565
NEOPLASIA
Global down-regulation of HOX gene expression in
PML-RAR + acute promyelocytic leukemia identified by
small-array real-time PCR
Alexander Thompson,
Michael
F. Quinn,
David Grimwade,
Claire M. O'Neill,
Momin R. Ahmed,
Sean Grimes,
Mary Frances McMullin,
Finbarr Cotter, and
Terence R. J. Lappin
From the Department of Haematology, Cancer Research
Centre, Queen's University, Belfast, Northern Ireland; the Division of
Medical and Molecular Genetics, Guy's, King's & St Thomas'
School of Medicine, London; Department of Experimental
Haematology and Medicine, St Bartholomew's; and The Royal London
Hospital, London, United Kingdom.
Acute promyelocytic leukemia (APL) is associated with a reciprocal
and balanced translocation involving the retinoic acid receptor-
(RAR). All-trans retinoic acid (ATRA) is
used to treat APL and is a potent morphogen that regulates
HOX gene expression in embryogenesis and organogenesis.
HOX genes are also involved in hematopoiesis and
leukemogenesis. Thirty-nine mammalian HOX genes have been
identified and classified into 13 paralogous groups clustered on 4 chromosomes. They encode a complex network of transcription regulatory
proteins whose precise targets remain poorly understood. The overall
function of the network appears to be dictated by gene dosage. To
investigate the mechanisms involved in HOX gene regulation
in hematopoiesis and leukemogenesis by precise measurement of
individual HOX genes, a small-array real-time
HOX (SMART-HOX) quantitative polymerase chain
reaction (PCR) platform was designed and validated. Application of
SMART-HOX to 16 APL bone marrow samples revealed a global
down-regulation of 26 HOX genes compared with normal
controls. HOX gene expression was also altered during differentiation induced by ATRA in the
PML-RAR+ NB4 cell line. PML-RAR fusion
proteins have been reported to act as part of a repressor complex
during myeloid cell differentiation, and a model linking
HOX gene expression to this PML-RAR repressor complex is
now proposed.
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