Correlation study between bone marrow and peripheral blood mesenchymal stem cells, cancerous plasma cells and reticulated platelets and disease variables of prognostic value in patients with multiple myeloma DONACIÓN

Normal and pathological hematopoiesis efficiency depends on a highly orchestrated biological system that responds to different interactions between hematopoietic stem cells (HSCs) and/or cancer cells with other resident populations within the bone marrow. Particularly, in the bone marrow¿s microenvironment mesenchymal stem cells (MSCs) stand out, due to their role as precursors of other stromal cells, such as osteoblasts and adipocytes that regulate physiological HSC quiescence, self-renewal and maintenance (1, 2). Furthermore, they regulate survival, chemoresistance and metastasis of hematological tumor cells (3, 4). Likewise, various studies have demonstrated megakaryocytes, specifically platelets, contribute to normal HSC and their homing to other tumor cell tissues of hematological origin (5, 6). Henceforth, multiple myeloma (MM, plasma cell myeloma, plasmocytic myeloma, Kahler disease) is a hematological illness where the bone marrow plays a determinant role in its pathogenesis and progression. Multiple myeloma is an incurable hematologic tumor of plasmatic cells that corresponds to 10% of all hematopoietic system tumors. It has a high disabling morbidity, and represents approximately 20% of deaths associated with hematologic system tumors (7). According to the Global Cancer Observatory in 2018, the incidence of MM in Colombia was of 2.3 cases per 100,000 habitants. Slightly lower than countries with high incidence rates of this disease, such as the United States of America and Peru (incidence ¿ 2.9). In Colombia 1,323 new MM cases and 806 deaths were registered (http://gco.iarc.fr/today/data/factsheets/populations/170-colombia-fact-sheets.pdf). In MM stratification systems allow to classify the stage of the disease and determine its prognosis (8). These include, Durie-Salmon, ISS (International Staging System) or-ISS (Revised International Staging System) and cytogenetic anomaly detection of t(4;14), t(14;16), t(14;20), amp1q21 and del17p, (8). However, physiopathological findings of this disease demonstrate its aggressiveness not only depends on the biological behavior and/or mutations of tumor plasma cells (TPC), but on their clones and subclones, which are implicated in their origin and progression. Moreover, their pathological microenvironment within the bone marrow, includes populations of cells types such as MSCs, reticulated platelets, osteoblasts, osteoclasts, endothelial cells and cells of the immune system, which also participate in MM development. Specifically, MSCs, play a determinant role in MM pathophysiology, since TPCs induce biological alterations of MSCs, promoting in this cell type a stark increase in cytokine synthesis, such as IL-6, VEGF, IL-10 and SCF, which favor tumor cell proliferation. Furthermore, the phenomena of osteoclastogenesis is increased and MSCs differentiation into osteoblasts is inhibited; promoting osteolytic lesions, most frequent in this type of disease (9, 10). Additionally, it has been demonstrated MSCs increase TPCs survival through inhibition of signals associated with apoptosis (11, 12). Interestingly, it has been pointed out patients with cancer not submitted to treatment have an increase in endogenous MSCs that circulate in peripheral blood (13). However, in patients with MM no information regarding the usefulness of MSCs evaluation in disease progression or prognosis is available. Regarding the role platelets play in tumor progression, various investigations point out these cells promote tumor progression through aggregate formation that reduce immune cell access. Additionally, tumor cell adhesion to vascular endothelium is increased, facilitating extravasation phenomena, synthesizing lipid products from alpha-granules (during platelet activation) that increase tumor neovascularization and induce cells with metastatic tumor phenotype (14). In MM, the role platelets play in tumor maintenance through induction of tumor plasmocyte proliferation has been demonstrated, as well as an increase in IL-1ß expression, promoting tumor progression (15). In addition, it has been demonstrated in patients with MM, thrombopoietin production is elevated (16), which could favor thrombopoiesis, and thus reticulated platelets, which could be associated with the state of the tumor, as has been observed in patients with colorectal cancer (17); however, it has not been evaluated in patients with MM. With the development of this proposal it is intended to detect MSCs and TPCs in peripheral blood and bone marrow from patients with MM that attend the HUSI¿s Javeriana Oncologic Center, employing cytometry flow technology . In addition, reticulated platelets will be detected through state of the art optic dispersion using Abbot¿s Alinity ALignment. The results herein obtained, serve as a pilot study to establish possible correlations among cell populations in the bone marrow¿s microenvironment of patients with MM and variables with prognostic values, which are used and validated in the clinical practice. These variables are utilized in post-treatment follow-up that include bone marrow tumor load, evaluation of minimal residual disease, tumor cell genetic alterations and biochemical parameters, among others (7). Additionally, stem cell autologous pre-transplant in MM will be evaluated. With the development of this proposal it is intended to detect MSCs and TPCs in peripheral blood and bone marrow from patients with MM that attend the HUSI¿s Javeriana Oncologic Center, employing cytometry flow technology . In addition, reticulated platelets will be detected through state of the art optic dispersion using Abbot¿s Alinity ALignment. The results herein obtained, serve as a pilot study to establish possible correlations among cell populations in the bone marrow¿s microenvironment of patients with MM and variables with prognostic values, which are used and validated in the clinical practice. These variables are utilized in post-treatment follow-up that include bone marrow tumor load, evaluation of minimal residual disease, tumor cell genetic alterations and biochemical parameters, among others (7). Additionally, stem cell autologous pre-transplant in MM will be evaluated.