Subclassification of B-acute lymphoblastic leukemia according to age, immunophenotype and microenvironment, predicts MRD risk in Mexican children from vulnerable regions.

Introduction: The 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. Methods: By 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 discussion: Our 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.

Patient-Derived Bone Marrow Spheroids Reveal Leukemia-Initiating Cells Supported by Mesenchymal Hypoxic Niches in Pediatric B-ALL.

B-cell acute lymphoblastic leukemia (B-ALL) results from the expansion of malignant lymphoid precursors within the bone marrow (BM), where hematopoietic niches and microenvironmental signals provide leukemia-initiating cells (LICs) the conditions to survive, proliferate, initiate disease, and relapse. Normal and malignant lymphopoiesis are highly dependent on the BM microenvironment, particularly on CXCL12-abundant Reticular (CAR) cells, which provide a niche for maintenance of primitive cells. During B-ALL, leukemic cells hijack BM niches, creating a proinflammatory milieu incompetent to support normal hematopoiesis but favoring leukemic proliferation. Although the lack of a phenotypic stem cell hierarchy is apparent in B-ALL, LICs are a rare and quiescent population potentially responsible for chemoresistance and relapse. Here, we developed novel patient-derived leukemia spheroids (PDLS), an ex vivo avatar model, from mesenchymal stromal cells (MSCs) and primary B-ALL cells, to mimic specialized niche structures and cell-to-cell intercommunication promoting normal and malignant hematopoiesis in pediatric B-ALL. 3D MSC spheroids can recapitulate CAR niche-like hypoxic structures that produce high levels of CXCL10 and CXCL11. We found that PDLS were preferentially enriched with leukemia cells displaying functional properties of LICs, such as quiescence, low reactive oxygen species, drug resistance, high engraftment in immunodeficient mice, and long-term leukemogenesis. Moreover, the combination of PDLS and patient-derived xenografts confirmed a microenvironment-driven hierarchy in their leukemic potential. Importantly, transcriptional profiles of MSC derived from primary patient samples revealed two unique signatures (1), a CXCL12low inflammatory and leukemia expansion (ILE)-like niche, that likely supports leukemic burden, and (2) a CXCL11hi immune-suppressive and leukemia-initiating cell (SLIC)-like niche, where LICs are likely sustained. Interestingly, the CXCL11+ hypoxic zones were recapitulated within the PDLS that are capable of supporting LIC functions. Taken together, we have implemented a novel PDLS system that enriches and supports leukemia cells with stem cell features driven by CXCL11+ MSCs within hypoxic microenvironments capable of recapitulating key features, such as tumor reemergence after exposure to chemotherapy and tumor initiation. This system represents a unique opportunity for designing ex vivo personalized avatars for B-ALL patients to evaluate their own LIC pathobiology and drug sensitivity in the context of the tumor microenvironment.

Hematopoietic stem cell transplantation in Puebla, México. Traveled roadand goals achieved

Introduction: In México there are only 4 cities that have significantly active hematopoietic stem cell transplantation programs; onlyin 3 of those cities, the most important national public health institution IMSS (Mexican Social Security Institute) count with them. The cities where these programs are found are Mexico City, Monterrey and Puebla. Since the beginning of this decade, and before, the productivity of these transplant programs in this public health institution is low, performing on average 148 transplants every year. Results: In the span comprised between April 1995 and October 2016, we have performed 474 hematopoietic transplants in our hospital; 229 of them were allogeneic and 245 autologous, in adult and children population. This accumulated experience has allowed the implementation of all the variety of hematopoietic stem cell transplantation available in our country, this has opened up the opportunity, for the first time in our institution, the possibility to provide a donor for every patient who requires an hematopoietic transplant, overcoming the phase in which patients could not be submitted to the procedure for lack of a compatible donor. Conclusions: The goals achieved in our hospital confirm the feasibility in developing uninterrupted long term transplant programs in hospitals not specially equipped with technology nor abundant funds of the public health system in the national province, and it shows that this programs can be created and developed in hospitals with similar conditions to ours in México, Latin America and middle-low income countries(AU)

Introducción: en méxico solo cuatro ciudades cuentan con programas de trasplante hematopoyético significativamente activos y en solo tres los tiene el IMSS, la principal institución de salud del país: Monterrey, Puebla y la ciudad de México .La productividad de estos centros del sector público es muy baja, realizando en conjunto 148 trasplantes en promedio por año desde el principio de la década actual. Resultados: en el lapso comprendido entre abril de 1995 y octubre de 2016, se efectuaron 474 trasplantes hematopoyéticos en nuestro hospital; 229 de ellos fueron alogénicos y 245 fueron autólogos, en población adulta e infantil. Esta experiencia acumulada ha permitido la implementación de todas las variedades disponibles en el país de estos procedimientos, lo que ha generado, por vez primera en la institución, poder contar con un donante para todo paciente que requiera un trasplante hematopoyético; superándose la etapa en la que los enfermos no se sometían al procedimiento por falta de un donador compatible. Conclusiones: la actividad acumulada en nuestra unidad hospitalaria confirma la factibilidad de desarrollar programas ininterrumpidos, a largo plazo, de estos procedimientos terapéuticos en hospitales no especialmente dotados de tecnología ni presupuesto del sector público de la provincia nacional y denota que estos mismos programas pueden ser creados y desarrollados en nosocomios con condiciones similares al nuestro en diversos territorios de México, de Latinoamérica y de países con ingreso medio-bajo(AU)