Immune evasion by oncogenic proteins of acute myeloid leukemia

Abstract

Key Points• PML-RARA and AML1-ETO evade NK cell recognition by specifically downregulating the expression of CD48.• The findings are relevant to AML patients bearing these specific translocations.PML-RARA and AML1-ETO are important oncogenic fusion proteins that play a central role in transformation to acute myeloid leukemia (AML). Whether these fusion proteins render the tumor cells with immune evasion properties is unknown. Here we show that both oncogenic proteins specifically downregulate the expression of CD48, a ligand of the natural killer (NK) cell activating receptor 2B4, thereby leading to decreased killing by NK cells. We demonstrate that this process is histone deacetylase (HDAC)-dependent, that it is mediated through the downregulation of CD48 messenger RNA, and that treatment with HDAC inhibitors (HDACi) restores the expression of CD48. Furthermore, by using chromatin immuoprecepitation (ChIP) experiments, we show that AML1-ETO directly interacts with CD48. Finally, we show that AML patients who are carrying these specific translocations have low expression of CD48. (Blood. 2014;123(10):1535-1543 Introduction Acute myeloid leukemia (AML) is the most common acute leukemia in adults. 1 There are several types of AML (approximately 30%) that are characterized by chromosomal translocations, which generate oncogenic fusion proteins.2 Two of the most common translocations in AML are t(15:17), which gives rise to the fusion protein PML-RARA, and t(8:21), which generates the fusion protein RUNX1-RUNX1T1 (AML1-ETO).3,4 Although these fusion proteins were discovered more than 20 years ago, 5,6 it is not known whether they provide immune evasion properties to AML tumors.Over the past few decades it has been established that natural killer (NK) cells, which are part of the innate immune system, play an important role in killing cancerous cells, 7,8 and specifically AML cells. 9,10 Several studies have found that AML patients who received transplants from NK alloreactive donors had lower relapse rates and improved disease-free survival. [11][12][13] Furthermore, it was recently reported that the presence of the NK cell receptor KIR2DS1, in matched unrelated donors, is associated with distinct outcomes of allogeneic hematopoietic stem cell transplantation in AML patients. 14 Finally, it was shown in several studies that NK cell activity correlates with clinical parameters of AML patients. 15,16 Killing by NK cells is mediated by several killer receptors that recognize distinct ligands. [17][18][19][20][21][22][23][24] Several human killer receptors, such as NKp44 and NKp30, have no mouse orthologs, and others, such as 2B4, have a mouse ortholog protein with opposing functions. In humans, 2B4 functions as an activating receptor, [25][26][27] whereas in mice, it mainly functions as an inhibitory receptor. 28,29 However, in both cases it recognizes CD48. [25][26][27][28] Despite the crucial role played by NK cells in eliminating AML tumors, the NK cell recognition of AML tumor cells is impaired at several levels (r...

Survival in acute myeloid leukemia is associated with NKp44 splice variants

“…AML quickly progresses and can result in death within a few months if left untreated. [1, 2], [3], [4] One of the major cell populations involved in anti-AML immune responses is CD3 − CD56 + innate lymphoid NK cells. [5–11] It has been previously shown that the status of NK cells in AML is critical for patients’ survival and that AML leukemic cells can induce impaired NK cell function.…”

Expression, Function, and Molecular Properties of the Killer Receptor Ncr1-Noé

“…The cytotoxicity of YTS cells is primarily executed by 2B4 (40). Therefore, we prepared chimeric constructs containing the extracellular part of Ncr1 and the various Ncr1 mutants, fused to the transmembrane and cytoplasmic domains of 2B4 (named Ncr1 2B4, Ncr1 W32A 2B4, Ncr1 W32E 2B4, and Ncr1 W32R 2B4).…”

AML drug resistance: c-Myc comes into play

“…Hence, this is an oncogenetic alteration, probably acting through the nuclear factor kB pathway. More than 20 fusion partner genes have been describes so far, 9 as confirmed by Cheah et al 1 From a diagnostic point of view, these PDGFRB diseases present with a clinical picture of chronic myelomonocytic leukemia with eosinophilia, atypical chronic myelogenous leukemia, or myelodysplastic syndrome/ myeloproliferative neoplasm overlap disorders. Imatinib is considered a definitive treatment of PDGFR-activated diseases.…”

“…This strategy will have to be carefully examined because ongoing clinical studies have embarked novel chemotherapy combinations together with the methyltransferase inhibitor decitabine and HDACi that display complex functional consequences on AML functions in vitro. [8][9][10] Conflict-of-interest disclosure: The authors declare no competing financial interests. n Socioeconomic disparities in lymphoma In this issue of Blood, Tao et al provide a retrospective analysis of a large population-based data set to examine the relationships between socioeconomic status (SES), insurance status, demographic factors, and diffuse large B-cell lymphoma (DLBCL) disease-specific and overall survival.…”