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Accordingly, in a recent transcriptome analysis of AML cells from patients who relapsed following
transplantation, a transcription factor complex consisting of IRF8, MYB, MEF2C, and MEIS1 was found to
regulate MHC expression in AML, and combinatorial changes in their expression are essential for reduced
[34]
MHC expression at relapse . Interestingly, the authors found a small cell population with silenced MHC
expression at leukemia diagnosis, and concluded that, similar to resistant LSC populations, this population
[34]
may be selected after transplantation and can contribute to relapse . Overall, these mechanisms are
plausible explanations for why the treatment of patients who relapse post-transplantation is particularly
challenging. Identifying ways to overcome decreased MHC expression following transplantation is
underway. For example, a recent study using AML xenograft mouse models reported that MDM2 inhibition
can increase MHC-II production, and CD8+ T cells isolated from MDM2 inhibitor-treated primary AML
mice can eradicate disease in secondary recipients .
[35]
The role of regulatory T cells in the immunosuppressive microenvironment
The increased number and activity of regulatory T cells (Tregs) in the leukemic bone marrow renders the
bone marrow an immunosuppressive microenvironment due to their effects on effector and cytotoxic T cell
populations. Recent insights have identified mechanisms for increased Treg function in the AML
microenvironment, such as via increased expression and production of IFNγ by AML cells, leading to
[36]
upregulation of genes that promote differentiation into Tregs . Recognizing the correlation between
increased Treg numbers and poor AML outcomes, one group investigated the effects of Treg ablation on
leukemogenesis . Using Foxp3-DTR to ablate Tregs in mice, they observed prolonged survival in MLL-
[37]
AF9-induced AML mouse models and increased CD8+ T cell activity . As Treg ablation is likely not easily
[37]
transferrable to the clinic, they also identified additional ways to impede Treg accumulation in the leukemic
[37]
microenvironment in mice, including CCL3-CCR1/CCR5 and CXCL12-CXCR4 blockade . Importantly,
as increased regulatory T cell populations are also a predictor of AML relapse following transplantation , it
[27]
is critical to exploit mechanisms that decrease Treg numbers and function.

NK cell-mediated immune evasion mechanisms
AML cells can also evade detection by NK cells, which are canonically activated by the recognition of stress-
induced ligands on foreign cells . Similar to their evasion of T cells, AML cells can also evade NK-cell
[38]
recognition and elimination through multiple mechanisms, including (1) the reduced expression of stress-
induced ligands on AML cells; (2) increased expression of inhibitory receptors on NK cells to suppress NK
cell function; (3) the induction of the immunosuppressive environment to limit NK cell numbers and
function; and (4) activation of anti-apoptotic pathways to resist NK-cell induced cell death [39,40] . These NK-
cell evasion mechanisms, as well as strategies to target them, have been extensively reviewed
elsewhere [39,41-44] . For example, it was shown that epigenetic mechanisms mediate the silencing of NKG2D
ligands in AML, and that treatment with hypomethylating agents can increase their expression and
subsequent NK-cell recognition . Furthermore, pivotal work demonstrated that LSCs are immune
[45]
privileged through their lack of expression of NKG2D ligand, which is essential for NK-cell detection and
subsequent clearance . As NK2GD remains a hot target for immunotherapy in AML [47-49] , it is important to
[46]
appreciate that other mechanisms may be required to eliminate the LSC population.

Another mechanism that can mediate NK-cell evasion is CD48 silencing [50-52] . It was demonstrated that high
CD48 expression on AML cells is correlated with a favorable prognosis. However, in a subset of AML
[52]
patients, CD48 expression can be suppressed through enhanced methylation . Therefore, treatment with
[53]
hypomethylating agents may be able to increase CD48 expression to increase NK-cell killing . Overall,
understanding NK-cell evasion mechanisms is critical to overcoming immunotherapy resistance and
identifying targets for immunotherapy.