The KRAS-G12D mutation induces metabolic vulnerability in B-cell acute lymphoblastic leukemia

Yan Xu,Houshun Fang,Yao Chen,Yabin Tang,Huiying Sun,Ziqing Kong,Fan Yang,Renate Kirschner-Schwabe,Liang Zhu,Alex Toker,Ning Xiao,Bin-Bing S Zhou,Hui Li

doi:10.1016/j.isci.2022.103881

Abstract

SummaryMutations in RAS pathway genes are highly prevalent in acute lymphoblastic leukemia (ALL). However, the effects of RAS mutations on ALL cell growth have not been experimentally characterized, and effective RAS-targeting therapies are being sought after. Here, we found that Reh ALL cells bearing the KRAS-G12D mutation showed increased proliferation rates in vitro but displayed severely compromised growth in mice. Exploring this divergence, proliferation assays with multiple ALL cell lines revealed that the KRAS-G12D rewired methionine and arginine metabolism. Isotope tracing results showed that KRAS-G12D promotes catabolism of methionine and arginine to support anabolism of polyamines and proline, respectively. Chemical inhibition of polyamine biosynthesis selectively killed KRAS-G12D B-ALL cells. Finally, chemically inhibiting AKT/mTOR signaling abrogated the altered amino acid metabolism and strongly promoted the in vivo growth of KRAS-G12D cells in B-ALL xenograft. Our study thus illustrates how hyperactivated AKT/mTOR signaling exerts distinct impacts on hematological malignancies vs. solid tumors.

Highlights

Mutations in RAS pathway proteins (e.g., KRAS, NRAS, FLT3, PTPN11, and NF1) are highly prevalent in acute lymphoblastic leukemia (ALL), with such mutations occurring in 40%–50% of pediatric B cell ALL cases (Irving et al, 2014; Jerchel et al, 2018; Oshima et al, 2016; Zhang et al, 2011)
B-ALL cells expressing the KRAS-G12D mutant display compromised growth under nutrientlimited conditions To explore the potential impacts of RAS pathway mutations in B-ALL, we expressed a canonical hotspot KRAS-G12D mutation or an empty vector (‘‘Ctrl’’ in text) in the human B-ALL cell line Reh
These results suggested that the KRAS-G12D mutation somehow alters the dependence of B-ALL cells on some nutrient(s) that may be limiting factors for continuous B-ALL cell growth

Summary

Introduction

Mutations in RAS pathway proteins (e.g., KRAS, NRAS, FLT3, PTPN11, and NF1) are highly prevalent in acute lymphoblastic leukemia (ALL), with such mutations occurring in 40%–50% of pediatric B cell ALL cases (Irving et al, 2014; Jerchel et al, 2018; Oshima et al, 2016; Zhang et al, 2011). It is known that RAS proteins can drive metabolic reprogramming to support rapid tumor growth (Najumudeen et al, 2021; Son et al, 2013; Ying et al, 2012), for example, leading to increased cellular demand for glucose and glutamine in pancreatic cancer (Son et al, 2013). There are several studies of solid tumors showing that oncogenic RAS can reprogram glucose metabolism in tumor cells to support rapid proliferation, increase glutamine utilization to provide extra energy, and enhance cysteine uptake to reduce oxidative stress (Hu et al, 2020; Najumudeen et al, 2021; Son et al, 2013; Ying et al, 2012; Yun et al, 2009). There have been very few experimental studies about how RAS mutations affect the growth of cells involved in hematological malignancies

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