M2 macrophages drive leukemic transformation by imposing resistance to phagocytosis and improving mitochondrial metabolism.

It is increasingly becoming clear that cancers are a symbiosis of diverse cell types and tumor clones. Combined single-cell RNA sequencing, flow cytometry, and immunohistochemistry studies of the innate immune compartment in the bone marrow of patients with acute myeloid leukemia (AML) reveal a shift toward a tumor-supportive M2-polarized macrophage landscape with an altered transcriptional program, with enhanced fatty acid oxidation and NAD+ generation. Functionally, these AML-associated macrophages display decreased phagocytic activity and intra-bone marrow coinjection of M2 macrophages together with leukemic blasts strongly enhances in vivo transformation potential. A 2-day in vitro exposure to M2 macrophages results in the accumulation of CALRlow leukemic blast cells, which are now protected against phagocytosis. Moreover, M2-exposed "trained" leukemic blasts display increased mitochondrial metabolism, in part mediated via mitochondrial transfer. Our study provides insight into the mechanisms by which the immune landscape contributes to aggressive leukemia development and provides alternatives for targeting strategies aimed at the tumor microenvironment.

Molecular-Based Score inspired on metabolic signature improves prognostic stratification for myelodysplastic syndrome.

Deregulated cellular energetics is formally incorporated as an emerging hallmark of cancer, however little is known about its processes in myelodysplastic syndromes (MDS). Using transcriptomic data of CD34+ cells from 159 MDS patients and 17 healthy donors, we selected 37 genes involved in cellular energetics and interrogated about its clinical and prognostic functions. Based on the low expression of ACLY, ANPEP, and PANK1, as well as high expression of PKM and SLC25A5, we constructed our Molecular-Based Score (MBS), that efficiently discriminated patients at three risks groups: favourable risk (n = 28; 3-year overall survival (OS): 100%); intermediate (n = 60; 76% [62-93%]) and adverse (n = 71; 35% [17-61%]). Adverse MBS risk was independently associated with inferior OS (HR = 10.1 [95% CI 1.26-81]; P = 0.029) in multivariable analysis using age, gender and the revised international prognostic score system as confounders. Transcriptional signature revealed that Favourable- and intermediate-risk patients presented enriched molecular programs related to mature myeloid progenitors, cell cycle progression, and oxidative phosphorylation, indicating that this cells differs in their origin, metabolic state, and cell cycle regulation, in comparison to the adverse-risk. Our study provides the first evidence that cellular energetics is transcriptionally deregulated in MDS CD34+ cells and establishes a new useful prognostic score based on the expression of five genes.

A multicenter comparative acute myeloid leukemia study: can we explain the differences in the outcomes in resource-constrained settings?

Outcomes in acute myeloid leukemia (AML) are dependent on patient- and disease-characteristics, treatment, and socioeconomic factors. AML outcomes between resource-constrained and developed countries have not been compared directly. We analyzed two cohorts: from São Paulo state, Brazil (USP, n = 312) and Oxford, United Kingdom (OUH, n = 158). USP cohort had inferior 5-year overall survival compared with OUH (29% vs. 49%, adjusted-p=.027). USP patients have higher early-mortality (23% vs. 6% p<.001) primarily due to multi-resistant Gram-negative bacterial and fungal infections. USP had higher 5-year cumulative incidence of relapse (60% vs. 50%, p=.0022), were less likely to undergo hematopoietic stem cell transplant (HSCT) (28% vs. 75%, p<.001) and waited longer for HSCT (median, 23.8 vs. 7.2 months, p<.001). Three-year survival in relapsed patients was worse in USP than OUH (10% vs. 39%, p<.001). Our study indicates that efforts to improve AML outcomes in Brazil should focus on infection prevention and control, and access to HSCT.

NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia.

Non-T cell activation linker (NTAL) is a lipid raft-membrane protein expressed by normal and leukemic cells and involved in cell signaling. In acute promyelocytic leukemia (APL), NTAL depletion from lipid rafts decreases cell viability through regulation of the Akt/PI3K pathway. The role of NTAL in APL cell processes, and its association with clinical outcome, has not, however, been established. Here, we show that reduced levels of NTAL were associated with increased all-trans retinoic acid (ATRA)-induced differentiation, generation of reactive oxygen species, and mitochondrial dysfunction. Additionally, NTAL-knockdown (NTAL-KD) in APL cell lines led to activation of Ras, inhibition of Akt/mTOR pathways, and increased expression of autophagy markers, leading to an increased apoptosis rate following arsenic trioxide treatment. Furthermore, NTAL-KD in NB4 cells decreased the tumor burden in (NOD scid gamma) NSG mice, suggesting its implication in tumor growth. A retrospective analysis of NTAL expression in a cohort of patients treated with ATRA and anthracyclines, revealed that NTAL overexpression was associated with a high leukocyte count (P = 0.007) and was independently associated with shorter overall survival (Hazard Ratio: 3.6; 95% Confidence Interval: 1.17-11.28; P = 0.026). Taken together, our data highlights the importance of NTAL in APL cell survival and response to treatment.

Integrating clinical features with genetic factors enhances survival prediction for adults with acute myeloid leukemia.

The 2017 European LeukemiaNet 2017 acute myeloid leukemia (AML) risk stratification (ELN2017) is widely used for risk-stratifying patients with AML. However, its applicability in low- and middle-income countries is limited because of a lack of full cytogenetic and molecular information at diagnosis. Here, we propose an alternative for risk stratification (the Adapted Genetic Risk [AGR]), which permits cytogenetic or molecular missing data while retaining prognostic power. We first analyzed 167 intensively treated patients with nonacute promyelocytic leukemia AML enrolled in São Paulo, Brazil (Faculdade de Medicina da Universidade de São Paulo), as our training data set, using ELN2017 as the standard for comparison with our AGR. Next, we combined our AGR with clinical prognostic parameters found in a Cox proportional hazards model to create a novel scoring system (survival AML score, SAMLS) that stratifies patients with newly diagnosed AML. Finally, we have used 2 independent test cohorts, Faculdade de Medicina de Ribeirão Preto (FMRP; Brazil, n = 145) and Oxford University Hospitals (OUH; United Kingdom, n = 157) for validating our findings. AGR was statistically significant for overall survival (OS) in both test cohorts (FMRP, P = .037; OUH, P = .012) and disease-free survival in FMRP (P = .04). The clinical prognostic features in SAMLS were age (>45 years), white blood cell count (<1.5 or >30.0 × 103/µL), and low albumin levels (<3.8 g/dL), which were associated with worse OS in all 3 cohorts. SAMLS showed a significant difference in OS in the training cohort (P < .001) and test cohorts (FMRP, P = .0018; OUH, P < .001). Therefore, SAMLS, which incorporates the novel AGR evaluation with clinical parameters, is an accurate tool for AML risk assessment.