Subversion of Systemic Glucose Metabolism as a Mechanism to Support the Growth of Leukemia Cells

Abstract

Summary From an organismal perspective, cancer cell populations can be considered analogous to parasites that compete with the host for essential systemic resources such as glucose. Here, we employed leukemia models and human leukemia samples to document a form of adaptive homeostasis, where malignant cells alter systemic physiology through impairment of both host insulin sensitivity and insulin secretion to provide tumors with increased glucose. Mechanistically, tumor cells induce high level production of IGFBP1 from adipose tissue to mediate insulin sensitivity. Further, leukemia-induced gut dysbiosis, serotonin loss and incretin inactivation combine to suppress insulin secretion. Importantly, attenuated disease progression and prolonged survival are achieved through disruption of the leukemia-induced adaptive homeostasis. Our studies provide a paradigm for systemic management of leukemic disease. Ye et al. show that leukemia cells hijack host glucose by inducing IGFBP1 production from adipose tissue to mediate insulin sensitivity and by inducing gut dysbiosis, serotonin loss, and incretin inactivation to suppress insulin secretion. Disrupting this adaptive homeostasis attenuates leukemia progression.

JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms

“…insulin levels and insulin resistance. 38 In contrast, our mutant JAK2 models displayed a more profound hypoglycemia without signs of insulin resistance, implying that acute myeloid leukemia and MPN cells differ in type and extent of the metabolic reprograming. Hypoglycemia strongly correlated with degree of increased erythropoiesis, consistent with the critical role of glucose metabolism in normal erythropoiesis.…”

Metabolic dependencies and vulnerabilities in leukemia

“…Moreover, 2-DG synergizes with prednisolone in these glucocorticoid-resistant cells and induces apoptosis, supporting a role for the inhibition of glycolysis in rendering ALL cells more sensitive to glucocorticoid treatment (Hulleman et al 2009). Finally, systemic regulation of glucose levels in the context of AML has been proposed as a mechanism favoring glucose uptake by myeloblasts (Ye et al 2018). Mechanistically, AML can increase serum levels of Insulin-like growth factor binding protein 1 (IGFBP1), which results in desensitization of normal tissues to insulin, decreasing their glucose uptake.…”

The Hepatic Microenvironment Uniquely Protects Leukemia Cells through Induction of Growth and Survival Pathways Mediated by LIPG

“…The two translocations were detected by co-expression of green fluorescent protein (GFP) and yellow fluorescent protein (YFP) respectively. In this model, our previous studies using PET-CT scanning indicate that liver is infiltrated with a large amount of leukemia cells (10). Indeed, histological analyses demonstrated extensive hepatic infiltration of leukemia cells ( Supplementary Fig.…”

“…Metabolism can strongly influence the growth and drug sensitivity of leukemia cells (7,10,11). (12,13) and therefore possess unique functions.…”