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Mutant PRPS1: a new therapeutic target in relapsed acute lymphoblastic leukemia

Nature Medicine volume 21, pages 553–554 (2015)Cite this article

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A new study identifies recurrent mutations in the purine biosynthesis gene phosphoribosyl pyrophosphate synthetase 1 (PRPS1) in relapsed acute lymphoblastic leukemia (ALL). This work highlights the importance of this pathway in the pathogenesis of relapse and suggests an approach to predicting and circumventing resistance in ALL.

ALL is the most common childhood tumor, and it comprises a diverse range of B-progenitor or T-lineage leukemias, each of which has a distinct signature of genetic alterations that drive tumorigenesis and influence treatment responsiveness1. Despite impressive advances in overall survival rates of childhood ALL, which now exceed 85% in the developed world, relapse remains unacceptably frequent, and it is commonly refractory to therapy and fatal2. Consequently, relapsed ALL is a leading cause of childhood cancer death, and identification of the biological basis of treatment failure is crucial to predicting relapse risk and to aiding in the development of new therapeutic strategies that avoid or treat relapse. Historically, the risk of relapse has been assigned to individual patients using a limited number of clinical and laboratory features at the time of diagnosis: age, male sex, elevated peripheral blood leukocyte (leukemic cell) count, extent of infiltration of the central nervous system, and the presence of recurring chromosomal alterations in leukemic cells3. However, the presence of high-risk chromosomal rearrangements such as those in the BCR-ABL1 fusion gene and in MLL (mixed-lineage leukemia; officially known as KMT2A) does not fully explain the likelihood of relapse.

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Figure 1: The role of PRPS1 mutations in the pathogenesis of relapse in ALL.

Kim Caesar/Nature Publishing Group

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  1. Charles G. Mullighan is in the Department of Pathology and the Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.,

    Charles G Mullighan

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  1. Charles G Mullighan
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Correspondence to Charles G Mullighan.

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Mullighan, C. Mutant PRPS1: a new therapeutic target in relapsed acute lymphoblastic leukemia. Nat Med 21, 553–554 (2015). https://doi.org/10.1038/nm.3876

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