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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 3

Loss of a porphyrin transporter, Abcg2, impairs MYCN self-renewal and enhances leukemic survival.

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Loss of a porphyrin transporter, Abcg2, impairs MYCN self-renewal and en...
(A) Scheme depicting the relationship among ABCG2, MYCN, and heme biosynthesis. 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, ABCG2 and MYCN. MYCN and Ponceau S images are the same as in Figure 1E. Representative images of 2 experiments. FTC, ABCG2 inhibitor; SA, succinylacetone (an inhibitor of heme synthesis); N-MPP, N-methyl-protoporphyrin IX (an inhibitor of ferrochelatase [Fech]). (B) Abcg2 is highly expressed in LSK and GMP (data obtained by combining 5 mice). (C) Abcg2-KO LSKs transduced with MYCN showed defective replating activity (experiment was repeated twice, with MC values obtained from 2 independent determinations per experiment; values are an aggregate mean ± SD). (D) MYCN-transduced Abcg2-KO progenitors do not have a defect in mitochondrial respiration or ATP generation (n = 3, mean ± SEM). (E) Defective self-renewal in LSKs at MC1 is accompanied by a decrease in the number of progenitors (5 mice were used per time point; results are representative of 2 independent experiments). (F) Abcg2-KO Lin– MYCN leukemic progenitors produced reduced LSK (G) but not CMP and (H) reduced GMP compared with WT (representative data from 2 independent experiments, with 5 mice per time point). (I) Abcg2-KO LSK MYCN progenitors display delayed disease progression (n = 5, mean ± SEM, 2-way ANOVA) and (J) increased survival (n = 10). *P < 0.05, log-rank Mantel Cox.

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