The role of RAS effectors in BCR/ABL induced chronic myelogenous leukemia

Abstract

BCR/ABL is the causative agent of chronic myelogenous leukemia (CML). Through structure/function analysis, several protein motifs have been determined to be important for the development of leukemogenesis. Tyrosine177 of BCR is a Grb2 binding site required for BCR/ABL-induced CML in mice. In the current study, we use a mouse bone marrow transduction/transplantation system to demonstrate that addition of oncogenic NRAS (NRASG12D) to a vector containing a BCR/ABL^Y177F mutant “rescues” the CML phenotype rapidly and efficiently. To further narrow down the pathways downstream of RAS that are responsible for this rescue effect, we utilize well-characterized RAS effector loop mutants and determine that the RAL pathway is important for rapid induction of CML. Inhibition of this pathway by a dominant negative RAL is capable of delaying disease progression. Results from the present study support the notion of RAL inhibition as a potential therapy for BCR/ABL-induced CML.

Keywords

BCR/ABL / chronic myelogenous leukemia (CML) / RAS / RAL

References

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Acknowledgements

This work is supported by the National Natural Science Foundation of China (Grant No. 81230055), Shanghai Excellent Science Leader Program (No. 12XD1403500), and the National Natural Science Foundation of China (Grant No. 81230055; to R.R.).

Compliance with ethics guidelines

Jessica Fredericks and Ruibao Ren declare that they have no conflicts of interest. All institutional and national guidelines for the care and use of laboratory animals were followed.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg