Background: Aberrant immunophenotype, characterized by the expression of lineage-inappropriate antigens on leukemic blasts, is associated with early relapse and a poor survival rate in Acute Lymphoblastic Leukemia (ALL). Early relapse gives a bad prognosis for ALL. This study evaluated the association between aberrant immunophenotype and Overall Survival (OS) and Disease-Free Survival (DFS) up to 18 months following the diagnosis of ALL. Materials and Methods: A retrospective cohort study was conducted to identify aberrant immunophenotype in 156 patients under 18 years of age with ALL. In this study, done at a tertiary level hospital, OS and DFS were analyzed using the Kaplan-Meier method, the Breslow test and a Cox regression model, with hazard ratios to determine the variables associated with mortality and relapse over an 18-month follow-up period. Results: The mean age at diagnosis was 6.5 years, and 57% of the patients were male. Aberrant immunophenotype was expressed in 87 patients. After 18 months of follow-up, 41 patients had died. The CD123 antigen was mostly associated with relapses (p=0.010). CD66c and CD123 co-expression decreased OS (p=0.040) and DFS (p=0.003). The univariate analysis demonstrated that CD66c and CD123 co-expression (p=0.005), single CD123 expression (p=0.001), and positive Measurable Residual Disease (MRD) (p=0.001) increased the risk of relapse. In a multivariable analysis, only risk stratification and MRD remained as independent predictors of OS and DFS. Conclusion: CD66c and CD123 co-expression was associated with decreased OS and DFS and a higher risk of relapse. However, this association did not remain significant in the multivariate model, indicating that it is not an independent prognostic factor. Nonetheless, isolated CD123 expression was linked to positive MRD and an increased risk of relapse. These observations provide clinically relevant preliminary insights, particularly in settings with survival disparities. These require confirmation in larger cohorts with extended follow-up and integrated molecular data.

IntroductionPediatric acute leukemia is the most common childhood malignancy and one of the leading causes of cancer-related mortality worldwide, particularly, in low- and middle-income countries (LMICs), where treatment abandonment remains a major barrier to survival. Geographic accessibility and socioeconomic conditions are recognized determinants, but their combined influence in Mexico remains understudied. This study evaluated the association between geographic accessibility, socioeconomic factors, and treatment abandonment among children with acute leukemia in south-central Mexico.MethodsA prospective cohort study was conducted in Oaxaca, Puebla, and Tlaxcala from 2021 to 2023, including 574 children under 18 years diagnosed with acute lymphoblastic or myeloid leukemia. Geographic accessibility was estimated using travel distance and time from patients' residences to referral hospitals, calculated with ORS Tools in QGIS. Socioeconomic variables included public health insurance affiliation, parental education and occupation, and number of siblings. Treatment abandonment was defined per SIOP criteria as failure to initiate or discontinuation of treatment for ≥4 consecutive weeks. Multivariable logistic regression, adjusted for child's sex, age, year of diagnosis, and leukemia subtype, was used to assess associations.ResultsTreatment abandonment occurred in 16.6% of patients. In multivariable analysis, lack of public health insurance (aOR = 2.83; 95% CI: 1.39-5.76; P < 0.01) and living ≥141 km from the hospital (aOR = 1.68; 95% CI: 1.02-2.74; P = 0.03) were significantly associated with abandonment. Other factors, including number of siblings, maternal education, and fathers' occupation, were not statistically significant.ConclusionLack of public health insurance and greater distance to the hospital are key determinants of treatment abandonment in children with acute leukemia in south-central Mexico. Expanding insurance coverage, reducing indirect costs, and addressing geographic barriers are critical to improve treatment adherence and survival outcomes in this population.

Acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease where current clinical practice guidelines remain focused on traditional cytogenetic markers. Despite recent advances demonstrating excellent diagnostic accuracy for gene expression signatures, a discontinuity exists between biomarker validation and clinical implementation. This study aimed to develop and validate a multiparametric gene expression signature using digital PCR (dPCR) to accurately diagnose pediatric ALL, with potential utility for monitoring measurable residual disease (MRD). We analyzed 130 bone marrow aspirates from pediatric patients from four clinical groups: non-leukemia, MRD-negative, MRD-positive and leukemia characterized by immunophenotype. Gene expression of an 8-gene panel (JUP, MYC, NT5C3B, GATA3, PTK7, CNP, ICOSLG, and SNAI1) was quantified by dPCR. The diagnostic performance of individual markers was assessed, and a Random Forest machine learning model was trained to classify active disease. The model was validated using a 5-fold stratified cross-validation approach. Individual markers, particularly JUP, MYC, and NT5C3B, showed good diagnostic accuracy for distinguishing leukemia from non-leukemia. However, integrating all eight markers into a multivariate Random Forest model significantly enhanced performance. The model achieved a mean cross-validated area under the curve (AUC) of 0.908 (±0.041) on receiver operator characteristic (ROC) analysis and 0.961 (±0.019) on Precision-Recall (PR) analysis, demonstrating high reliability and a favorable balance between sensitivity and precision. The integrated model achieved high sensitivity (88.9%) for detecting active disease, particularly at initial diagnosis. Although specificity was moderate (65.0%), the high positive predictive value (PPV 85.1%) and accuracy (81.5%) confirm the clinical utility of a positive result. While the panel showed promising performance for distinguishing MRD-positive from MRD-negative samples, the limited MRD-positive cohort size (n = 11) indicates that validation in larger MRD-focused studies is required before clinical implementation for treatment monitoring. This dPCR-based platform provides accessible, quantitative detection without requiring knowledge of clonal shifts or specific genomic landscape, offering potential advantages for resource-limited settings such as those represented in our Mexican pediatric cohort.

Background/Objectives: Acute leukemia, the most common childhood cancer, poses a significant public health challenge in low- and middle-income countries (LMICs) due to its high incidence and mortality rates. Survival rates in these regions are often lower, primarily due to delayed and inaccurate diagnoses, limited access to treatment, therapy abandonment, therapy-related toxicity, and inadequate healthcare infrastructure. In Mexico, a new initiative called OncoCREAN has been developed to address this urgent need by establishing local treatment centers near pediatric patients’ home cities, ensuring timely cancer detection and comprehensive disease treatment. Methods: A retrospective observational study was conducted on pediatric patients treated at the Mexican Social Security Institute (IMSS) between 18 May 2022 and 30 June 2025. Patients presenting clinical suspicion of acute leukemia were referred to OncoCREAN centers for sample collection and subsequent shipment to the Oncoimmunology and Cytomics Laboratory (OCL), where immunophenotyping confirmed the diagnoses. Results: The implementation of the OncoCREAN model significantly reduced diagnostic turnaround times, facilitating timely therapeutic decisions, minimized uncertainty, and optimized clinical management. The decentralized framework demonstrated feasibility across diverse geographic regions, ensuring access to advanced diagnostic technology for vulnerable populations and generating valuable data on disease incidence and molecular profiles. Conclusions: The OncoCREAN model highlights the critical importance of decentralizing high-technology diagnostic resources in modern pediatric oncology. This new approach to translational research that is accessible, inclusive, and relevant to society creates a paradigm shift in the management of childhood cancer and other diseases.

Background/Objectives: B-cell precursor acute lymphoblastic leukemia (B-ALL), the most common pediatric acute leukemia (AL), is frequently characterized by aberrant antigen expression, which aids diagnosis and prognosis. The myeloid antigen CD66c is notably frequent in B-ALL and has been proposed as a marker of disease aggressiveness and treatment response. Evaluating CD66c in Mexican pediatric patients may provide insights into disease biology. Methods: A cohort of 128 pediatric patients was referred to the Laboratory of Oncoimmunology and Cytomics of Childhood Cancer (OCL) at Instituto Mexicano del Seguro Social (IMSS) for immunophenotyping tests between March 2022 and November 2023. Additionally, control bone marrow (BM) samples were assessed. Aberrant antigen expression in hematopoietic populations and BM microenvironment stroma phenotyping were performed. Results: In total, 84.38% of B-ALL patients exhibited aberrant expression of ≥1 myeloid antigen. Among CD66c-positive patients, 13.79% had detectable measurable residual disease (MRD) during follow-up and 20.69% died. Mesenchymal stromal cells (MSCs) from patients with positive or low CD66c expression displayed inflammatory profiles. ProB leukemias with low CD66c expression were more likely to exhibit detectable MRD, increased mortality, and reduced survival. Conclusions: Low CD66c expression induces molecular stealth that could favor immune evasion and niche persistence, thereby increasing the risk of relapse and therapeutic failure.

Background:Despite high cure rates for pediatric B-cell acute lymphoblastic leukemia (B-ALL) in high-income countries, early mortality remains unacceptably high in low- and middle-income countries (LMICs), largely due to limited access to risk-adapted therapy and response monitoring. Southern Mexico, a region marked by socioeconomic vulnerability, is emblematic of this disparity. In 2022 the Childhood Cancer Cytomics Laboratory (CCCL) started the implementation of standardized protocols for immunophenotyping and measurable residual disease (MRD) monitoring of B-ALL patients from this region. Objective:To evaluate the impact of implementing standardized immunophenotyping and MRD monitoring on early mortality in children with B-ALL treated in public hospitals in southern Mexico. Methods:A prospective cohort study was conducted between 2022 and 2024. Before initiating CCCL activities, public hospitals were invited to participate, and standardized protocols for sample collection, handling, and transportation were implemented across all participating sites. A total of 298 children newly diagnosed with B-ALL were enrolled and followed throughout treatment. Patients were stratified based on whether immunophenotyping and MRD monitoring were performed at the CCCL. MRD was assessed at the end of induction (EOI) therapy using standardized EuroFlow-based flow cytometry protocols. Simultaneously, early mortality-defined as death occurring within the first year after diagnosis-was evaluated. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) were estimated using multivariable Cox regression, with p-values < 0.05 considered statistically significant. Results:Early mortality was significantly lower among patients who underwent MRD monitoring at the CCCL (10.8%) compared to those who did not (24.8%, p<0.01). One-year overall survival was also higher in patients evaluated at the CCCL (89.6% vs. 75.2%, p<0.001). In the multivariable Cox regression analysis, patients who underwent MRD monitoring at the CCCL showed a significantly lower risk of early mortality during the first year of treatment (adjusted hazard ratio [aHR] 0.41; 95% CI: 0.22-0.77; p < 0.01), after adjusting for sex, NCI risk classification, treatment abandonment, and early relapse. MRD positivity was associated with a CD34+ ProB immunophenotype, suggesting a more treatment-resistant leukemic profile. Conclusion:Centralized, standardized MRD monitoring at the CCCL was associated with a reduction in early mortality and improved one-year survival in children with B-ALL from a socioeconomically vulnerable population. These findings demonstrate the clinical value and feasibility of implementing MRD-informed response assessment in LMICs and highlight the potential of centralized diagnostic platforms to reduce survival disparities in childhood leukemia.

The fight against mortality in pediatric oncohematological diseases is a story of human rights, academia, innovation, and technological advancement-one in which women in science have played a pivotal role. With talent, perseverance, and sensitivity, they greatly contributed to research in new cellular therapies, expanding the frontiers of treatment and giving the most vulnerable patients the gift of more years of life. This review explores multipotent and unipotent cell therapies, focusing on hematopoietic stem cell transplantation (HSCT), mesenchymal stromal cell transplantation (MSCT), and chimeric antigen receptor (CAR)-T cell and natural killer (NK) cell therapy. HSCT remains the gold standard for high-risk and relapsed cases, with graft sources including bone marrow (BM), mobilized peripheral blood (MPB), and umbilical cord blood (UCB). Advances in MSCT highlight its role in hematopoiesis support and immunomodulation, reducing graft-versus-host disease (GVHD) risks. CAR-T cell therapy has revolutionized leukemia treatment, although challenges such as antigen escape, T-cell exhaustion, and treatment resistance persist. Emerging strategies, including CAR-NK cells, seek to enhance efficacy while minimizing toxicity. Despite these advancements, cell therapy remains complex and resource-intensive, necessitating further innovations for broader accessibility, particularly in developing regions.

IntroductionThe decisive key to disease-free survival in B-cell precursor acute lymphoblastic leukemia in children, is the combination of diagnostic timeliness and treatment efficacy, guided by accurate patient risk stratification. Implementation of standardized and high-precision diagnostic/prognostic systems is particularly important in the most marginalized geographic areas in Mexico, where high numbers of the pediatric population resides and the highest relapse and early death rates due to acute leukemias are recorded even in those cases diagnosed as standard risk.MethodsBy using a multidimensional and integrated analysis of the immunophenotype of leukemic cells, the immunological context and the tumor microenvironment, this study aim to capture the snapshot of acute leukemia at disease debut of a cohort of Mexican children from vulnerable regions in Puebla, Oaxaca and Tlaxcala and its potential use in risk stratification.Results and discussionOur findings highlight the existence of a distinct profile of ProB-ALL in children older than 10 years, which is associated with a six-fold increase in the risk of developing measurable residual disease (MRD). Along with the absence of CD34+ seminal cells for normal hematopoiesis, this ProB-ALL subtype exhibited several characteristics related to poor prognosis, including the high expression level of myeloid lineage markers such as MPO and CD33, as well as upregulation of CD19, CD34, CD24, CD20 and nuTdT. In contrast, it showed a trend towards decreased expression of CD9, CD81, CD123, CD13, CD15 and CD21. Of note, the mesenchymal stromal cell compartment constituting their leukemic niche in the bone marrow, displayed characteristics of potential suppressive microenvironment, such as the expression of Gal9 and IDO1, and the absence of the chemokine CXCL11. Accordingly, adaptive immunity components were poorly represented. Taken together, our results suggest, for the first time, that a biologically distinct subtype of ProB-ALL emerges in vulnerable adolescents, with a high risk of developing MRD. Rigorous research on potential enhancing factors, environmental or lifestyle, is crucial for its detection and prevention. The use of the reported profile for early risk stratification is suggested.

The main objective of the National Project for Research and Incidence of Childhood Leukemias is to reduce early mortality rates for these neoplasms in the vulnerable regions of Mexico. This project was conducted in the states of Oaxaca, Puebla, and Tlaxcala. A key strategy of the project is the implementation of an effective roadmap to ensure that leukemia patients are the target of maximum benefit of interdisciplinary collaboration between researchers, clinicians, surveyors, and laboratories. This strategy guarantees the comprehensive management of diagnosis and follow-up samples of pediatric patients with leukemia, centralizing, managing, and analyzing the information collected. Additionally, it allows for a precise diagnosis and monitoring of the disease through immunophenotype and measurable residual disease (MRD) studies, enhancing research and supporting informed clinical decisions for the first time in these regions through a population-based study. This initiative has significantly improved the diagnostic capacity of leukemia in girls, boys, and adolescents in the regions of Oaxaca, Puebla, and Tlaxcala, providing comprehensive, high-quality care with full coverage in the region. Likewise, it has strengthened collaboration between health institutions, researchers, and professionals in the sector, which contributes to reducing the impact of the disease on the community.

En 2005 se publicaron recomendaciones para la tipificación de hemopatías malignas en Latinoamérica.Se consideró necesario realizar una reunión nacional para actualizarlas.Se convocaron y reunieron 95 profesionales expertos en el tema para analizar y contrastar alternativas y llegar a un consenso.Se alcanzaron opiniones de consenso en lo relativo a indicaciones, tipos y manejo de muestras, anticuerpos, nomenclatura e informe de resultados para el diagnóstico y seguimiento de las leucemias agudas.Las recomendaciones se describen en este artículo y se hace hincapié en la necesidad de que los laboratorios nacionales se apeguen a ellas.

Background and Aims. Mexico is among the countries with the highest estimated excess mortality rates due to the COVID-19 pandemic, with more than half of reported deaths occurring in adults younger than 65 years old. Although this behavior is presumably influenced by the young demographics and the high prevalence of metabolic diseases, the underlying mechanisms have not been determined.Methods. The age-stratified case fatality rate (CFR) was estimated in a prospective cohort with 245 hospitalized COVID-19 cases, followed through time, for the period October 2020-September 2021. Cellular and inflammatory parameters were exhaustively investigated in blood samples by laboratory test, multiparametric flow cytometry and multiplex immunoassays.Results. The CFR was 35.51%, with 55.2% of deaths recorded in middle-aged adults. On admission, hematological cell differentiation, physiological stress and inflammation parameters, showed distinctive profiles of potential prognostic value in patients under 65 at 7 days follow-up.Pre-existing metabolic conditions were identified as risk factors of poor outcomes. Chronic kidney disease (CKD), as single comorbidity or in combination with diabetes, had the highest risk for COVID-19 fatality. Of note, fatal outcomes in middle-aged patients were marked from admission by an inflammatory landscape and emergency myeloid hematopoiesis at the expense of functional lymphoid innate cells for antiviral immunosurveillance, including NK and dendritic cell subsets.Conclusions. Comorbidities increased the development of imbalanced myeloid pheno-type, rendering middle-aged individuals unable to effectively control SARS-CoV-2. A predictive signature of high-risk outcomes at day 7 of disease evolution as a tool for their early stratification in vulnerable populations is proposed. (c) 2023 The Authors. Published by Elsevier Inc. on behalf of Instituto Mexicano del Seguro Social (IMSS). This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Leukemogenesis is proposed to result from the continuous interplay between inducive bone marrow (BM) microenvironments and malignant precursor cells. Recent findings point toward an abnormal production of proinflammatory mediators within the BM from acute lymphoblastic leukemia (ALL) patients, although the mechanism underlying this phenomenon is uncertain. Here, we have identified 3 miRNAs, miR-146a-5p, miR-181b-5p, and miR-199b-3p, as potential candidates for TLR8 ligation, which are overexpressed in ALL and show agonist functional binding. When purified from ALL exosomes, they demonstrated their capacity of inducing cytokine production by both, hematopoietic and stromal BM cells. Of note, the exposure of BM cells from ALL patients to the proinflammatory milieu resulting from these miRNAs agonist activity revealed the proliferation of normal progenitors, while poor effects were recorded in the leukemic counterpart. The unconventional roles of the tumor-secreted miRNAs as TLR8 agonist ligands may provide a novel mechanism contributing a tumor-microenvironment feedback loop by switching on proinflammatory pathways that further activate normal hematopoietic precursors and support ALL progression. Secreted B-ALL TLR8-agonist miRNAs are involved in the promotion of proinflammatory microenvironments that target normal hematopoietic cells. B-lineage ALL cells secrete exosomes containing miRNAs endowed with the ability of functionally binding TLR8 in hematopoietic and BM mesenchymal stromal cells. Upon TLR8 signaling, the activation of the NF-kB pathway induces secretion of proinflammatory cytokines that, in turn, promotes cell proliferation in early hematopoietic cell populations, driving a tumor-microenvironment-hematopoietic activation feedback loop that may reduce the normal hematopoietic stem and progenitor cell compartment and facilitate cancer progression.

Inflammation, a regulatory mechanism crucial for the homeostasis and maintenance of the hematopoietic system, is capable of playing pathogenic roles that ultimately cooperate in malignant progression. Its continuous and multilevel interplay with inducing microenvironments and genetically aberrant leukemia initiating cells within the bone marrow, can create a stable triad structure present from the earliest stages of tumor emergence. This review aims to discuss the most recent advances in the essential functions of inflammatory signals in both, steady-state and malignant hematopoiesis. By shedding more light on the mechanisms underlying the expansion and maintenance of malignant primitive cells under aberrant activating microenvironments, it may contribute to a comprehensive understanding of the leukemia pathobiology. New strategies to intervene the dynamic intercommunication between components of the inflammation-microenvironment-leukemia initiating cell triad would be of crucial relevance for an integral control of hematological malignancies.

Background. In vitro methods for hematopoietic differentiation of human pluripotent stem cells (hPSC) are a matter of priority for the in-depth research into the mechanisms of early embryogenesis. So-far, published results regarding the generation of hematopoietic cells come from studies using either 2D or 3D culture formats, hence, it is difficult to discern their particular contribution to the development of the concept of a unique in vitro model in close resemblance to in vivo hematopoiesis. Aim of the study. To assess using the same culture conditions and the same time course, the potential of each of these two formats to support differentiation of human pluripotent stem cells to primitive hematopoiesis without exogenous activation of Wnt signaling. Methods. We used in parallel 2D and 3D formats, the same culture environment and assay methods (flow cytometry, IF, qPCR) to investigate stages of commitment and specification of mesodermal, and hemogenic endothelial cells to CD34 hematopoietic cells and evaluated their clonogenic capacity in a CFU system. Results. We show an adequate formation of mesoderm, an efficient commitment to hemogenic endothelium, a higher number of CD34 hematopoietic cells, and colony-forming capacity potential only in the 3D format-supported differentiation. Conclusions. This study shows that the 3D but not the 2D format ensures the induction and realization by endogenous mechanisms of human pluripotent stem cells’ intrinsic differentiation program to primitive hematopoietic cells. We propose that the 3D format provides an adequate level of upregulation of the endogenous Wnt/β-catenin signaling.

Breast cancer (BC) is the leading cause of cancer-related death in women in the world. Since tumor cells employ autophagy as a survival pathway, it has been proposed that autophagy inhibition could be beneficial for cancer treatment. There are several onging clinical trials where autophagy is being inhibited (using chloroquine, CQ or hydroxychloroquine, HCQ) along with chemotherapy with promising results. However, there is also in vitro evidence in which autophagy inhibition can induce epithelial to mesenchymal transition (EMT) in cancer cells, indicating that, at least in some cases, this strategy could be detrimental for cancer patients. In this study, we found that the genetic inhibition of autophagy primed cells for EMT by inducing a decrease in E-cadherin protein levels, while CQ treatment decreased E-cadherin levels, induced morphological changes related to EMT, increased EMT-related transcription factor (EMT-TF) expression and migration in estrogen receptor positive (ER +) BC cell lines. Importantly, CQ treatment increased intracellular reactive oxygen species (ROS) which induced the secretion of macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine related to malignancy. Both ROS production and MIF secretion were responsible for the mesenchymal morphology and increased migratory capacity induced by CQ. Our results indicate that CQ treatment increased malignancy by inducing ROS production, MIF secretion and EMT and suggest that autophagy inhibition in ER + BC patients might have detrimental effects. Our data indicates that a careful selection of patients should be performed in order to determine who will benefit the most from autophagy inhibition with available pharmacological agents for the treatment of breast cancer.

Breast cancer is the main cause of cancer-related death in women in the world. Because autophagy is a known survival pathway for cancer cells, its inhibition is currently being explored in clinical trials for treating several types of malignancies. In breast cancer, autophagy has been shown to be necessary for the survival of cancer cells from the triple negative subtype (TNBC), which has the worst prognosis among breast cancers and currently has limited therapeutic options. Autophagy has also been involved in the regulation of protein secretion and, of importance for this work, the inhibition of autophagy is known to promote the secretion of proinflammatory cytokines from distinct cell types. We found that the inhibition of autophagy in TNBC cell lines induced the secretion of the macrophage migration inhibitory factor (MIF), a pro-tumorigenic cytokine involved in breast cancer invasion and immunomodulation. MIF secretion was dependent on an increase in reactive oxygen species (ROS) induced by the inhibition of autophagy. Importantly, MIF secreted from autophagy-deficient cells increased the migration of cells not treated with autophagy inhibitors, indicating that autophagy inhibition in cancer cells promoted malignancy in neighboring cells through the release of secreted factors, and that a combinatorial approach should be evaluated for cancer therapy.

Due to their crucial role in cell metabolism and homeostasis, alterations in mitochondrial biology and function have been related to the progression of diverse diseases including cancer. One of the consequences associated to mitochondrial dysfunction is the production of reactive oxygen species (ROS). ROS are known to have a controversial role during cancer initiation and progression and although several studies have tried to manipulate intracellular ROS levels using antioxidants or pro-oxidation conditions, it is not yet clear how to target oxidation for cancer therapy. In this study, we found differences in mitochondrial morphology in breast cancer cells when compared to a non-tumorigenic cell line and differences in mitochondrial function among breast cancer subtypes when exploring gene-expression data from the TCGA tumor dataset. Interestingly, we found increased ROS levels in triple negative breast cancer (TNBC) cell lines and a dependency on ROS for survival since antioxidant treatment induced cell death in TNBC cells but not in an estrogen receptor positive (ER+) cell line. Moreover, we identified the mitochondria as the main source of ROS in TNBC cell lines. Our results indicate a potential use for ROS as a target for therapy in the TNBC subtype which currently has the worst prognosis among all breast cancers and remains as the only breast cancer subtype which lacks a targeted therapy.

Due to their increasing rates of morbidity and mortality, childhood malignancies are considered a global health priority, with acute lymphoblastic leukemias (ALLs) showing the highest incidence worldwide. Control of malignant clone emergence and the subsequent normal-leukemic hematopoietic cell out-competition require antitumor monitoring mechanisms. Investigation of cancer surveillance innate cells may be critical to understand the mechanisms contributing in either disease progression or relapse, and to promote displacement of leukemic hematopoiesis by the normal counterpart. We report here that NK cell production is less and low hematopoietic progenitor numbers contribute to this defect. By investigating the expression of the activation molecule class I restricted T-cell associated molecule (CRTAM) along the hematopoietic lineage differentiation pathway, we have identified lymphoid precursor populations coexpressing CD34, CD56/CD3/CD19, and CRTAM as the earliest developmental stage where activation may take place in specialized niches that display the ligand nectin-like-2. Of note, bone marrow (BM) from patients with ALL revealed high contents of preactivated CD56high NK cells expressing CRTAM and endowed with an exhaustion-like phenotype and the functional capability of producing IL-10 and TGF-β in vitro. Our findings suggest, for the first time, that the tumor microenvironment in ALL directly contribute to exhaustion of NK cell functions by the CRTAM/Necl-2 interaction, and that the potential regulatory role of exhausted-like NK cells may favor malignant progression at the expense of anti-tumor responses. Phenotypic and functional identity of this unique suppressor-like NK cell population within the leukemic BM would be of special interest for the pathobiology of ALL and development of targeting strategies.