Terminal differentiation of bone marrow NK cells and increased circulation of TIGIT + NK cells may be related to poor outcome in acute myeloid leukemia

2021 ◽  
Author(s):  
Xiangbo Zeng ◽  
Danlin Yao ◽  
Lian Liu ◽  
Yikai Zhang ◽  
Jing Lai ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Terminal Differentiation ◽  
Poor Outcome ◽  
Acute Myeloid

scholarly journals Single-cell profiling reveals the trajectories of natural killer cell differentiation in bone marrow and a stress signature induced by acute myeloid leukemia

2020 ◽  
Author(s):  
Adeline Crinier ◽  
Pierre-Yves Dumas ◽  
Bertrand Escalière ◽  
Christelle Piperoglou ◽  
Laurine Gil ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Single Cell ◽  
Natural Killer ◽  
Rna Sequencing ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Single Cell Rna Sequencing ◽  
Acute Myeloid

SummaryNatural killer (NK) cells are innate cytotoxic lymphoid cells (ILCs) involved in the killing of infected and tumor cells. Among human and mouse NK cells from the spleen and blood, we previously identified by single-cell RNA sequencing (scRNAseq) two similar major subsets, NK1 and NK2. Using the same technology, we report here the identification, by single-cell RNA sequencing (scRNAseq), of three NK cell subpopulations in human bone marrow. Pseudotime analysis identified a subset of resident CD56bright NK cells, NK0 cells, as the precursor of both circulating CD56dim NK1-like NK cells and CD56bright NK2-like NK cells in human bone marrow and spleen under physiological conditions. Transcriptomic profiles of bone marrow NK cells from patients with acute myeloid leukemia (AML) exhibited stress-induced repression of NK cell effector functions, highlighting the profound impact of this disease on NK cell heterogeneity. Bone marrow NK cells from AML patients exhibited reduced levels of CD160, but the CD160high group had a significantly higher survival rate.

Analysis of NK Cells Receptors and NK Cells Ligands in Acute Myeloid Leukemia: Comparisons Between the Blood and the Bone Marrow.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1643-1643
Author(s):  
Jerome Rey ◽  
Eloise Perrot ◽  
Caroline Veuillen ◽  
Thomas Prébet ◽  
Anne Etienne ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Healthy Volunteers ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Immune Escape ◽  
Flow Cytometry Data ◽  
Nk Receptor ◽  
Acute Myeloid

Abstract Abstract 1643 Poster Board I-669 Background The significant role of NK cells in the control of acute myeloid leukemia (AML) has been demonstrated in the setting of allogeneic stem cell transplantation. However, the implication of NK cells against autologous leukemic cells needs to be clarified. We have previously described deficient expression of NK activatory receptors in AML at diagnosis, in particular the natural cytotoxicity receptors (NCR) namely NKp30 and NKp46. So, defective cytotoxicity of AML cells can be explained by abnormalities of activating NK-receptor expression allowing immune escape from NK cells. However, immune escape can be also due to defective activating NK receptor-ligand interactions due to abnormal expression of their ligands on blasts cells. These defects have been observed in particular on NK cells or blasts cells isolated from the blood. Few studies have analysed the bone marrow component although blasts cells concentrate here. We postulated that abnormalities of NK cells receptors or ligands expression are more severe in bone marrow, in near contact with the blasts, compared with blood. We sought to identify disparities between deficient expression of NK or ligands in the bone marrow in comparison with the blood. Methods We realized a phenotypic analysis of NK cells and blasts cells at the diagnosis of AML. The level of activatory NK receptors (NKRa) knew to mediate NK cell recognition and lysis of AML blasts cells (NCR (NKp30 and NKp46) and DNAM-1) was investigated by flow cytometry. The expression of NKG2D ligands (MICA/B and ULBP1-3) and DNAM-1 ligands (Nectin-2 and PVR) receptors were also analysed. These analyses were realised with coupled specimens obtained in the same patient at diagnosis of AML (n=19), peripheral blood and bone marrow samples in order to detect discrepancies between these two sites. A control group (age-matched; n=15) for blood samples was included for this study. All biological samples were obtained from patients and healthy volunteers after informed consent. Results A total of 19 patients were included in this study. We included 6 cases of AML 5, 4 cases of AML 4, 4 cases of AML 2, 4 cases of AML 1 and one case of AML 0. Flow cytometry data for NKRa were only available for 11 patients. We confirmed the deficient expression of NKp30 and NKp46 receptors (as determined by MFI) on NK cells from blood of AML patients. In AML patient, the ratio MFI (MFI receptor/MFI control isotype) of NKp30 (4.27 +/- 2.97; p<0.0001) and of NKp46 (5.96 +/- 5.67; p<0.0001) significantly differed from healthy volunteers (NKp30 26.65 +/- 6.12; NKp46 39.73 +/- 9.66). Moreover, the deficient expression of these receptors was also observed on NK cells from the bone marrow (NKp30 3.66 +/- 2.22, p<0.0001; NKp46 6.71+/- 6.42, p<0.0001). However, we can not demonstrated significant differences between the NKRa expression on NK cells from blood versus from bone marrow (NKp30 p= 0.8438; NKp46 p= 0.9476 and DNAM-1 p= 0.3579). The expression of the ligands for NKRa was analysed to compare the expression on blasts cells isolated from the blood compared to blasts cells isolated from the bone marrow. Flow cytometry data for ligands were only available for 17 patients. We observed a strong expression of HLA class I molecules on blasts cells that was equivalent in the blood and in bone marrow. DNAM-1 ligands (PVR, Nectin 2) were expressed on blasts cells (see figure). NKG2D ligands were also expressed but to a lesser extent with predominant ULBP1 expression. However, we can not observed significant differences in the expression of ligands between the blood and the bone marrow. Conclusions The deficiency of activating NK cells receptors expression at AML diagnosis is significant, present in a majority of patients, and consistent across the 2 components, ie blood and bone marrow. These defects are one component of the immune escape from NK cells. We have speculated that these abnormalities were more pronounced in bone marrow, near blasts cells, because these abnormalities are in part induced by blasts cells. However, we can not demonstrated significant differences in the expression of activating receptors or ligands between blood and bone marrow. We are accumulating more data in order to detect differences between sub-groups of AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals Bone marrow infiltrated natural killer cells predicted the anti-leukemia activity of MCL1 or BCL2 inhibitors in acute myeloid leukemia

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Yu-Jun Dai ◽  
Si-Yuan He ◽  
Fang Hu ◽  
Xue-Ping Li ◽  
Jian-Ming Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Natural Killer ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Treatment Strategies ◽  
Leukemia Treatment ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is still incurable due to its heterogeneity and complexity of tumor microenvironment. It is imperative therefore to understand the molecular pathogenesis of AML and identify leukemia-associated biomarkers to formulate effective treatment strategies. Here, we systematically analyzed the clinical characters and natural killer (NK) cells portion in seventy newly-diagnosis (ND) AML patients. We found that the proportion of NK cells in the bone marrow of ND-AML patients could predict the prognosis of patients by analyzing the types and expression abundance of NK related ligands in tumor cells. Furthermore, MCL1 inhibitor but not BCL2 inhibitor combined with NK cell-based immunotherapy could effectively improve the therapeutic efficiency via inhibiting proliferation and inducing apoptosis of AML primary cells as well as cell lines in vitro. There results provide valuable insights that could help for exploring new therapeutic strategies for leukemia treatment.

Expanded Natural Killer Cells for Cellular Therapy of Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2743-2743 ◽  
Author(s):  
Hiroyuki Fujisaki ◽  
Harumi Kakuda ◽  
Timothy Lockey ◽  
Paul W. Eldridge ◽  
Wing Leung ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Expansion ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Target Cells ◽  
Healthy Donors ◽  
Acute Myeloid

Abstract Approximately half of the patients with acute myeloid leukemia (AML) harbor occult disease during therapy, leading to overt relapse. Novel treatments are needed to advance cure rates. AML cells are sensitive to natural killer (NK) cell cytotoxicity if they express HLA Class I molecules that do not bind killer-inhibitory receptors (KIR) on NK cells. The demonstration that haploidentical NK cells can expand in vivo and exert anti-AML activity when infused after non-myeloablative conditioning (Miller et al., Blood105: 3051, 2005), provided impetus to further explore their clinical potential and develop ways to increase their efficacy. The success of NK cell therapy depends on: i) mismatch in recipient HLA and donor KIR phenotype, allowing NK cell alloreactivity; ii) infusion of sufficient numbers of NK cells to achieve an effector: target (E:T) ratio that produces a significant leukemia cytoreduction. We found that K562 cells genetically modified to express membrane-bound IL-15 and 4-1BB ligand (K562-mb15-41BBL) induced expansion of human NK cells (Imai et al., Blood106: 376, 2005). In the present study, we first tested the stimulatory capacity of irradiated K562-mb15-41BBL in 34 additional healthy donors: CD56+ CD3− NK cell expansion after 7–10 days of culture was 5–87 fold (median, 22); after 21 days, NK cells could expand >1000 fold. CD3+ T cells expanded minimally or not at all. NK cells derived from 12 healthy donors were tested against the AML cell lines K562, KG-1, U937 and HL-60. Expanded NK cells were consistently cytotoxic at low E:T ratios. Thus, mean (± SD) cytotoxicity after 4 hrs at 4: 1 was 85.1% ± 8.7% for K562, 83.7% ± 9.4% for KG-1, 78.8% ± 15.2% for U937 and 94.8% ± 5.1% for HL-60. Expanded NK cells were effective even when outnumbered by target cells: at a 0.5: 1 ratio, cytotoxicities were 34.1% ± 14.7% with K562, 51.5% ± 16.5% with KG-1, 24.5% ± 14.8% with U937 and 52.1% ± 9.8% with HL-60. We next tested cytotoxicity of expanded NK cells from 10 donors against primary cells obtained from the bone marrow of 9 newly diagnosed patients with AML. Median cytotoxicity after 4 hrs of culture at a 4: 1 ratio was high, although interdonor variability was observed, with cytoxicities ranging from 22% to 90%. When expanded NK cells were cultured for 7 days with primary AML cells in the presence of bone marrow mesenchymal cells (to prevent spontaneous apoptosis of the AML cells) we could detect cytotoxicity at a 0.01:1 E:T ratio. Expanded NK cells were consistently more cytotoxic than primary NK cells from the same donor. Gene expression studies revealed marked changes in expression of adhesion molecules and cytokine transcripts after expansion. Expanded NK cells exerted considerable antileukemic effect in NOD-SCID-IL2Rgammanull mice engrafted with human AML cells, providing a strong rationale for their clinical testing. To this end, the K562-mb15-41BBL stimulatory cell line is currently being made under cGMP conditions and conditions for large-scale NK cell expansion have been established in support of a pilot protocol in which expanded haploidentical NK cells with be administered to patients with refractory AML.

Enasidenib: First Mutant IDH2 Inhibitor for the Treatment of Refractory and Relapsed Acute Myeloid Leukemia

2019 ◽  
Vol 18 (14) ◽  
pp. 1936-1951 ◽  
Author(s):  
Raghav Dogra ◽  
Rohit Bhatia ◽  
Ravi Shankar ◽  
Parveen Bansal ◽  
Ravindra K. Rawal
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Adverse Effects ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
White Blood Cells ◽  
Phase Iii ◽  
Acute Myeloid

Background: Acute myeloid leukemia is the collective name for different types of leukemias of myeloid origin affecting blood and bone marrow. The overproduction of immature myeloblasts (white blood cells) is the characteristic feature of AML, thus flooding the bone marrow and reducing its capacity to produce normal blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly known as AG-221 which is being marketed under the name Idhifa to treat R/R AML with IDH2 mutation. The present review depicts the broad profile of enasidenib including various aspects of chemistry, preclinical, clinical studies, pharmacokinetics, mode of action and toxicity studies. Methods: Various reports and research articles have been referred to summarize different aspects related to chemistry and pharmacokinetics of enasidenib. Clinical data was collected from various recently published clinical reports including clinical trial outcomes. Result: The various findings of enasidenib revealed that it has been designed to allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also presented good safety and efficacy profile along with 9.3 months overall survival rates of patients in which disease has relapsed. The drug is still under study either in combination or solely to treat hematological malignancies. Molecular modeling studies revealed that enasidenib binds to its target through hydrophobic interaction and hydrogen bonding inside the binding pocket. Enasidenib is found to be associated with certain adverse effects like elevated bilirubin level, diarrhea, differentiation syndrome, decreased potassium and calcium levels, etc. Conclusion: Enasidenib or AG-221was introduced by FDA as an anticancer agent which was developed as a first in class, a selective allosteric inhibitor of the tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. Phase III trial on the Enasidenib is still under process along with another trial to test its potency against other cell lines. Edasidenib is associated with certain adverse effects, which can be reduced by investigators by designing its newer derivatives on the basis of SAR studies. Hence, it may come in the light as a potent lead entity for anticancer treatment in the coming years.

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