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Blood, 15 January 2007, Vol. 109, No. 2, pp. 740-746.
Prepublished online as a Blood First Edition Paper on September 12, 2006; DOI 10.1182/blood-2006-04-019588.
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Submitted April 25, 2006
Accepted August 19, 2006
Relationship of expression of aquaglyceroporin 9 with arsenic uptake and sensitivity in leukemia cells
Jordy Leung, Annie Pang, Wai-Hung Yuen, Y. L. Kwong*, and Eric W.C. Tse
Department of Medicine, University of Hong Kong
Department of Medicine, Univeristy of Hong Kong
Department of Chemistry, University of Hong Kong
* Corresponding author; email: ylkwong{at}hkucc.hku.hk.
Arsenic trioxide (As2O3) is highly efficacious in acute promyelocytic leukemia (APL). Aquaglyceroporin 9 (AQP9) is a trans-membrane protein that may be involved in arsenic uptake. In 10/11 myeloid and lymphoid leukemia lines, quantitative polymerase chain reaction (Q-PCR) and Western blotting showed that AQP9 expression correlated positively with As2O3-induced cytotoxicity. As a proof-of-principle, transfection of EGFP-tagged AQP9 to the hepatoma line Hep-3B, not expressing AQP9 and As2O3-insensitive, led to membrane AQP9 expression and increased As2O3-induced cytotoxicity. Similarly, the chronic myeloid leukemia line K562 expressed low levels of AQP9 and was As2O3-insensitive. The K562EGFP-AQP9 transfectant accumulated significantly higher intracellular arsenic than control K562EGFP when incubated with As2O3, resulting in significantly increased As2O3-induced cytotoxicity. Pre-treatment of the myeloid leukemia line HL-60 with all-trans retinoic acid (ATRA) up-regulated AQP9, leading to significantly increased arsenic uptake and As2O3-induced cytotoxicity on incubation with As2O3; which might explain the synergism between ATRA and As2O3. Therefore, AQP9 controlled arsenic transport and might determine As2O3-sensitivity. Q-PCR showed that primary APL cells expressed AQP9 significantly (2- 3 logs) higher than other acute myeloid leukemias (AML), which might explain their exquisite As2O3-sensitivity. However, APL and AML with maturation expressed comparable AQP9 levels, suggesting that AQP9 expression was related to granulocytic maturation.
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