Despite significant recent advances in our understanding of the biology and genetics of acute myeloid leukemia (AML), current AML therapies are mostly based on a backbone of standard chemotherapy ...which has remained mostly unchanged for over 20 years. Several novel therapies, mostly targeting neomorphic/activating recurrent mutations found in AML patients, have only recently been approved following encouraging results, thus providing the first evidence of a more precise and personalized approach to AML therapy. Rewired metabolism has been described as a hallmark of cancer and substantial evidence of its role in AML establishment and maintenance has been recently accrued in preclinical models. Interestingly, unique metabolic changes are generated by specific AML recurrent mutations or in response to diverse AML therapies, thus creating actionable metabolic vulnerabilities in specific patient groups. In this review we will discuss the current evidence supporting a role for rewired metabolism in AML pathogenesis and how these metabolic changes can be leveraged to develop novel personalized therapies.
Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we ...optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies.
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•Optimized CRISPR platform for identification of genome-wide genetic vulnerabilities•Catalog of genetic vulnerabilities in acute myeloid leukemia cell lines•KAT2A inhibition induces myeloid differentiation and apoptosis•KAT2A inhibition arrests the growth of primary AML cells, but not of normal progenitors
Tzelepis et al. optimize a CRISPR-Cas9-based platform for the performance of genome-wide recessive screens and apply it to identify genetic vulnerabilities of human AML cells. They identify several known therapeutic targets including BRD4, DOT1L, and MEN1, and numerous additional candidates. They provide data proposing KAT2A as a potential therapeutic target.
Hypoxia signals directly to chromatin via histone demethylases to alter gene expression
Approximately 2.6 billion years ago, during the Proterozoic period, the evolution of photosynthesis in ...cyanobacteria led to the introduction of the by-product of this reaction, oxygen, into Earth's atmosphere (
1
). This great oxidative event heralded the rise of multicellular organisms, which are almost totally dependent on oxygen as an efficient fuel for metabolism and as a cofactor in many critical physiological enzymatic reactions. Central to this adaptation, and to allow cellular physiology across a wide range of oxygen concentrations (tensions), metazoans have evolved the highly conserved hypoxia-inducible factor (HIF) pathway (
2
). This is important for both physiological and pathological processes that occur in a hypoxic microenvironment, including embryogenesis, stem cell homeostasis, cancer, and cardiovascular disease. It has long been observed that hypoxia induces histone lysine hypermethylation, a form of epigenetic chromatin modification. However, whether this represents a direct sensing of oxygen tension or an indirect effect, perhaps through the HIF pathway, has not been established (
3
). On pages 1222 and 1217 of this issue, Batie
et al.
(
4
) and Chakraborty
et al.
(
5
), respectively, resolve this question, demonstrating in different cellular systems that the activity of the lysine-specific demethylases (KDMs) KDM5A and KDM6A is oxygen sensitive, and thereby identifying them as oxygen sensors.
Epigenetic regulators, such as EZH2, are frequently mutated in cancer, and loss-of-function
mutations are common in myeloid malignancies. We have examined the importance of cellular context for Ezh2 ...loss during the evolution of acute myeloid leukemia (AML), where we observed stage-specific and diametrically opposite functions for Ezh2 at the early and late stages of disease. During disease maintenance, WT Ezh2 exerts an oncogenic function that may be therapeutically targeted. In contrast, Ezh2 acts as a tumor suppressor during AML induction. Transcriptional analysis explains this apparent paradox, demonstrating that loss of
derepresses different expression programs during disease induction and maintenance. During disease induction,
loss derepresses a subset of bivalent promoters that resolve toward gene activation, inducing a feto-oncogenic program that includes genes such as
, whose overexpression phenocopies
loss to accelerate AML induction in mouse models. Our data highlight the importance of cellular context and disease phase for the function of Ezh2 and its potential therapeutic implications.
Abstract There is a paucity of data that pertain to thrombosis in patients with hematological malignancies. Recent studies showed that patients with lymphoma, multiple myeloma, and acute leukemia ...have an increased thrombotic risk, particularly at the time of diagnosis and during chemotherapy. We searched the PubMed database for articles on thromboembolic complications in patients with hematological malignancies published between 1996 and 2013. The incidence of thrombotic events is variable, and is influenced by the type and the stage of hematological malignancy, the antitumor therapy, and the use of central venous devices. The pathogenesis of thromboembolic disease in hematological malignancies is multifactorial. Tumor cell-derived procoagulant, fibrinolytic, or proteolytic factors, and inflammatory cytokines affect clotting activation, and chemotherapy and immunomodulatory drugs increase the thrombotic risk in patients with lymphoma, acute leukemia, and multiple myeloma. Infections might also contribute to the pathogenesis of the thromboembolic complications: endotoxins from gram-negative bacteria induce the release of tissue factor, tumor necrosis factor and interleukin-1b, and gram-positive organisms can release bacterial mucopolysaccharides that directly activate factor XII. In the setting of plasma cell dyscrasias, hyperviscosity, decreased fibrinolysis, procoagulant autoantibody production, inflammatory cytokines, acquired activated protein C resistance, and the prothrombotic effects of antimyeloma agents might be the cause of thromboembolic complications. Anticoagulant therapy is very complicated because of high risk of hemorrhage. Therefore, an accurate estimate of a patient's thrombotic risk is essential to allow physicians to target thromboprophylaxis in high-risk patients.
Targeting the fusion oncoprotein BCR-ABL with tyrosine kinase inhibitors has significantly affected chronic myeloid leukemia (CML) treatment, transforming the life expectancy of patients; however the ...risk for relapse remains, due to persistence of leukemic stem cells (LSCs). Therefore it is imperative to explore the mechanisms that result in LSC survival and develop new therapeutic approaches. We now show that major histocompatibility complex (MHC)-II and its master regulator class II transactivator (CIITA) are downregulated in CML compared with non-CML stem/progenitor cells in a BCR-ABL kinase–independent manner. Interferon γ (IFN-γ) stimulation resulted in an upregulation of CIITA and MHC-II in CML stem/progenitor cells; however, the extent of IFN-γ-induced MHC-II upregulation was significantly lower than when compared with non-CML CD34+ cells. Interestingly, the expression levels of CIITA and MHC-II significantly increased when CML stem/progenitor cells were treated with the JAK1/2 inhibitor ruxolitinib (RUX). Moreover, mixed lymphocyte reactions revealed that exposure of CD34+ CML cells to IFN-γ or RUX significantly enhanced proliferation of the responder CD4+CD69+ T cells. Taken together, these data suggest that cytokine-driven JAK-mediated signals, provided by CML cells and/or the microenvironment, antagonize MHC-II expression, highlighting the potential for developing novel immunomodulatory-based therapies to enable host-mediated immunity to assist in the detection and eradication of CML stem/progenitor cells.
•MHC-II and its master regulator CIITA are downregulated in CML stem/progenitor cells in a BCR-ABL kinase–independent manner.•JAK1/2 inhibition increased MHC-II expression, suggesting elevation of CML immunogenicity may provide a way to reduce CML persistence.
Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain ...unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a premalignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation is attenuated. We also document that CREBBP mutations may occur in HSPCs from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies.
Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukaemia (AML) and is often driven by metabolic adaptations which are therapeutically actionable. Here ...we identify inhibition of mannose-6-phosphate isomerase (MPI), the first enzyme in the mannose metabolism pathway, as a sensitizer to both cytarabine and FLT3 inhibitors across multiple AML models. Mechanistically, we identify a connection between mannose metabolism and fatty acid metabolism, that is mediated via preferential activation of the ATF6 arm of the unfolded protein response (UPR). This in turn leads to cellular accumulation of polyunsaturated fatty acids, lipid peroxidation and ferroptotic cell death in AML cells. Our findings provide further support to the role of rewired metabolism in AML therapy resistance, unveil a connection between two apparently independent metabolic pathways and support further efforts to achieve eradication of therapy-resistant AML cells by sensitizing them to ferroptotic cell death.
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