NPM–RAR, not the RAR–NPM reciprocal t(5;17)(q35;q21) acute promyelocytic leukemia fusion protein, inhibits myeloid differentiation

Abstract

The t(5;17) variant of acute promyelocytic leukemia (APL) fuses the nucleophosmin (NPM) gene at 5q35 with the retinoic acid receptor alpha (RARA) at 17q12-22. We have previously shown that leukemic cells express both NPM–RAR and RAR– NPM reciprocal translocation products. In this study we investigated the potential role of both proteins in modulating myeloid differentiation. Expression of NPM–RAR inhibited vitamin D3/transforming growth factor β (TGFβ)-mediated differentiation of U937 cells by more than 50%. In contrast, RAR–NPM expression did not alter vitamin D3/TGFβ-induced differentiation of U937 clones. These results indicate that NPM–RAR, not RAR–NPM, is the prime mediator of myeloid differentiation arrest in t(5;17) APL.

Keywords::

• Acute promyelocytic leukemia
• U937
• differentiation
• NPM–RAR
• RAR–NPM
• nucleophosmin

Acknowledgements

The authors would like to thank Richard Steinman, MD, PhD and Daniel Johnson, PhD for valuable discussions. This work was supported by NIH R01 CA67346 and P30 CA047904.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.