Natural killer cell immune escape in acute myeloid leukemia

Lion, Eva; Willemen, Yannick; Berneman, Zwi N.; Tendeloo, Viggo F.I. Van; Smits, Evelien

doi:10.1038/leu.2012.87

Cited by 134 publications

(113 citation statements)

References 101 publications

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“…Multiple mechanisms of innate immune escape have been previously described in AML patients, including decreased NK cytotoxicity receptor (NCR) expression, increased inhibitory NKG2A expression, downregulation of NK-activating ligands, and secretion of soluble NK-inhibitory factors (5)(6)(7)(8)(9)(10). These mechanisms likely work in concert to render both autologous and transplanted NK cells ineffective at controlling AML blast outgrowth over time (3,11).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-29b mediates altered innate immune development in acute leukemia

Mundy-Bosse¹,

Scoville²,

Chen³

et al. 2016

Journal of Clinical Investigation

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Section: Introductionmentioning

confidence: 99%

MicroRNA-29b mediates altered innate immune development in acute leukemia

Mundy-Bosse¹,

Scoville²,

Chen³

et al. 2016

Journal of Clinical Investigation

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“…5 Patients with acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (MDS) face a particular pneumonia risk, as both disease and treatment impair immune function. [6][7][8][9][10][11] In the transfusion era, autopsy studies reveal that pneumonia is the most frequent cause of death among leukemia patients, 12,13 and recent studies find that the presence of pneumonia is the leading hazard for death during leukemia remission induction therapy.…”

Section: Introductionmentioning

confidence: 99%

Inducible epithelial resistance protects mice against leukemia-associated pneumonia

Leiva‐Juárez

Ware

Kulkarni

et al. 2016

Blood

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“…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 (reviewed in Lion et al 30 ). However, the mechanisms leading to the resistance of AML cells to NK cell killing are unclear, and it is also unknown whether the AML fusion proteins specifically provide immune resistance to AML cells.…”

Section: Introductionmentioning

confidence: 99%

Immune evasion by oncogenic proteins of acute myeloid leukemia

Elias¹,

Yamin²,

Golomb

et al. 2014

Blood

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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...

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Natural killer cell immune escape in acute myeloid leukemia

Cited by 134 publications

References 101 publications

MicroRNA-29b mediates altered innate immune development in acute leukemia

MicroRNA-29b mediates altered innate immune development in acute leukemia

Inducible epithelial resistance protects mice against leukemia-associated pneumonia

Immune evasion by oncogenic proteins of acute myeloid leukemia

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