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Upregulated heme biosynthesis, an exploitable vulnerability in MYCN-driven leukemogenesis
Yu Fukuda, … , Gerard Grosveld, John D. Schuetz
Yu Fukuda, … , Gerard Grosveld, John D. Schuetz
Published August 3, 2017
Citation Information: JCI Insight. 2017;2(15):e92409. https://doi.org/10.1172/jci.insight.92409.
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Research Article Metabolism

Upregulated heme biosynthesis, an exploitable vulnerability in MYCN-driven leukemogenesis

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Abstract

The increased heme biosynthesis long observed in leukemia was previously of unknown significance. Heme, synthesized from porphyrin precursors, plays a central role in oxygen metabolism and mitochondrial function, yet little is known about its role in leukemogenesis. Here, we show increased expression of heme biosynthetic genes, including UROD, only in pediatric AML samples that have high MYCN expression. High expression of both UROD and MYCN predicts poor overall survival and unfavorable outcomes in adult AML. Murine leukemic progenitors derived from hematopoietic progenitor cells (HPCs) overexpressing a MYCN cDNA (MYCN-HPCs) require heme/porphyrin biosynthesis, accompanied by increased oxygen consumption, to fully engage in self-renewal and oncogenic transformation. Blocking heme biosynthesis reduced mitochondrial oxygen consumption and markedly suppressed self-renewal. Leukemic progenitors rely on balanced production of heme and heme intermediates, the porphyrins. Porphyrin homeostasis is required because absence of the porphyrin exporter, ABCG2, increased death of leukemic progenitors in vitro and prolonged the survival of mice transplanted with Abcg2-KO MYCN-HPCs. Pediatric AML patients with elevated MYCN mRNA display strong activation of TP53 target genes. Abcg2-KO MYCN-HPCs were rescued from porphyrin toxicity by p53 loss. This vulnerability was exploited to show that treatment with a porphyrin precursor, coupled with the absence of ABCG2, blocked MYCN-driven leukemogenesis in vivo, thereby demonstrating that porphyrin homeostasis is a pathway crucial to MYCN leukemogenesis.

Authors

Yu Fukuda, Yao Wang, Shangli Lian, John Lynch, Shinjiro Nagai, Bruce Fanshawe, Ayten Kandilci, Laura J. Janke, Geoffrey Neale, Yiping Fan, Brian P. Sorrentino, Martine F. Roussel, Gerard Grosveld, John D. Schuetz

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Figure 1

Heme biosynthetic genes are upregulated in AML and UROD is a poor prognostic factor.

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Heme biosynthetic genes are upregulated in AML and UROD is a poor progno...
(A) In St. Jude Children’s Research Hospital pediatric AML patients, MYCN expression strongly correlated with upregulation of heme biosynthesis genes. See also Supplemental Figure 1A. (B) In adult AML patients, UROD and MYCN overexpression predicted poor overall survival, analyzed by log-rank Mantel Cox. (C) AML patients relapse or experience refractory disease more frequently when UROD and MYCN are highly expressed together, as determined by Fisher’s exact test. (D) A positive relationship between UROD and MYCN in AML or normal PBMCs from multiple data sets, as determined by linear regression. (E) Immunoblot analysis of murine hematopoietic progenitors transduced with either an empty vector or a virus expressing a MYCN expression vector, followed by immunoblot analysis of the displayed proteins, UROD and MYCN. Representative images of two experiments. MYCN and Ponceau S images are the same as in Figure 3A. *P < 0.05, **P < 0.01, ***P < 0.001.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

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