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Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia.

Leukemia, 2021/05;35(5):1267-1278.

Ge Z[1, 2], Song C[1, 3], Ding Y[1], Tan BH[1], Desai D[1], Sharma A[1], Gowda R[1], Yue F[1], Huang S[1], Spiegelman V[1], Payne JL[1, 4], Reeves ME[4], Iyer S[1], Dhanyamraju PK[1], Imamura Y[1], Bogush D[1], Bamme Y[1], Yang Y[3], Soliman M[1], Kane S[1], Dovat E[1], Schramm J[1], Hu T[1], McGrath M[1], Chroneos ZC[1], Payne KJ[4], Gowda C[5], Dovat S[6]

Affiliations

PMID: 33531656DOI: 10.1038/s41375-021-01132-5

Impact factor: 12.883

Abstract
Children of Hispanic/Latino ancestry have increased incidence of high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) with poor prognosis. This leukemia is characterized by a single-copy deletion of the IKZF1 (IKAROS) tumor suppressor and increased activation of the PI3K/AKT/mTOR pathway. This identifies mTOR as an attractive therapeutic target in HR B-ALL. Here, we report that IKAROS represses MTOR transcription and IKAROS' ability to repress MTOR in leukemia is impaired by oncogenic CK2 kinase. Treatment with the CK2 inhibitor, CX-4945, enhances IKAROS activity as a repressor of MTOR, resulting in reduced expression of MTOR in HR B-ALL. Thus, we designed a novel therapeutic approach that implements dual targeting of mTOR: direct inhibition of the mTOR protein (with rapamycin), in combination with IKAROS-mediated transcriptional repression of the MTOR gene (using the CK2 inhibitor, CX-4945). Combination treatment with rapamycin and CX-4945 shows synergistic therapeutic effects in vitro and in patient-derived xenografts from Hispanic/Latino children with HR B-ALL. These data suggest that such therapy has the potential to reduce the health disparity in HR B-ALL among Hispanic/Latino children. The dual targeting of oncogene transcription, combined with inhibition of the corresponding oncoprotein provides a paradigm for a novel precision medicine approach for treating hematological malignancies.
MeSH terms
Antineoplastic Agents; B-Lymphocytes; Casein Kinase II; Cell Line; Cell Line, Tumor; Child; Gene Expression Regulation, Leukemic; Genes, Tumor Suppressor; HEK293 Cells; Humans; Naphthyridines; Phenazines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Signal Transduction; TOR Serine-Threonine Kinases
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