Bone Marrow Soluble Immunological Mediators as Clinical Prognosis Biomarkers in B-Cell Acute Lymphoblastic Leukemia Patients Undergoing Induction Therapy

Abstract

Different factors are used as predictors of unfavorable clinical outcomes in B-Cell Acute Lymphoblastic Leukemia (B-ALL) patients. However, new prognostic markers are needed in order to allow treatment to be more accurate, providing better results and an improved quality of life. In the present study, we have characterized the profile of bone marrow soluble mediators as possible biomarkers for risk group stratification and minimal residual disease (MRD) detection during induction therapy. The study featured 47 newly-diagnosed B-cell acute lymphoblastic leukemia (B-ALL) patients that were categorized into subgroups during induction therapy according to risk stratification at day 15 [Low Risk (LR), Low Risk increasing to High Risk (LR→HR) and High Risk (HR)] and the MRD detection on day 35 (MRD(-) and MRD(+)). Soluble immunological mediators (CXCL8, CCL2, CXCL9, CCL5, CXCL10, IL-1β, IL-6, TNF, IFN-γ, IL-17A, IL-4, IL-5, IL-10 and IL-2) were quantified by cytometric bead array and ELISA. Our findings demonstrated that increased levels of CCL5, IFN-γ and IL-2 at baseline appeared as putative candidates of good prognosis in LR and MRD(-) subgroups, while CCL2 was identified as a consistent late biomarker associated with poor prognosis, which was observed on D35 in HR and MRD(+) subgroups. Furthermore, apparently controversial data regarding IL-17A and TNF did not allow the definition of these molecules as either positive or negative biomarkers. These results contribute to the search for novel prognostic indicators, and indicate the potential of bone marrow soluble mediators in prognosis and follow-up of B-ALL patients during induction therapy.

Systemic immunological profile of children with B-cell acute lymphoblastic leukemia: performance of cell populations and soluble mediators as serum biomarkers

“…We previously demonstrated that the network of soluble immunological mediators in the bone marrow can be an attractive source for investigation of potential prognostic biomarkers (17). However, it must be considered that the collection of bone marrow samples is a very invasive procedure, especially in pediatric populations.…”

“…The overall signature of the cell populations and soluble immunological mediators was determined according to Kerr et al (2021) (17), by converting the original results of each variable expressed as a continuous variable into categorical data, using the global median values obtained for the whole data universe from all participants (B-ALL patients on different days of induction therapy and the controls) as the cut-off to segregate patients with low and high frequency of cell populations, and chemokines and cytokines levels. The following cut-off points were used: NK=4.18; NKT=1.96; CD3 + T=64.40; CD4 + T=49.50; CD8 + T=37.10; Treg=2.88; CXCL8 = 1058.64; CCL2 = 628.35; CXCL9 = 2001.07; CCL5 = 209502.20; CXCL10 = 4846.97; IL-6 = 216.79; TNF=83.44; IFN-g=81.95; IL17A=81.95; IL-4 = 156.45; IL-10 = 123.67; and IL-2 = 137.08, expressed as a percentage for cell populations, and MFI for chemokines and cytokines.…”

“…In addition, studies have shown that characteristics related to the immunological profile, based on the levels of cytokines and chemokines, in addition to the frequency and phenotype of cell populations, can also be used as potential prognostic biomarkers in children and adults (10)(11)(12)(13)(14)(15). Furthermore, our studies have previously demonstrated, through characterization of the network of soluble immunological mediators in the bone marrow compartment, that particular mediators can provide valuable information about the stage of malignancy in relation to leukemic burden, risk group stratification, and detection of measurable residual disease (16,17).…”

Mesenchymal Stromal Cells (MSCs): An Ally of B-Cell Acute Lymphoblastic Leukemia (B-ALL) Cells in Disease Maintenance and Progression within the Bone Marrow Hematopoietic Niche

“…Concerning the possible impact on disease, they observed that CCL2 and CXCL8 were able to increase the adhesion of ALL cells to BM stromal cells and promote survival and proliferation of the latter, suggesting that the leukemic cells modulate the function of tumor-supportive BM-MSCs. Importantly, a study by Kerr and colleagues correlating BM chemokines levels with disease outcome identified CCL2 as a late biomarker of poor prognosis [ 80 ].…”

The Yin-Yang of myeloid cells in the leukemic microenvironment: Immunological role and clinical implications

“…It is important to note that CCL2 also regulates the infiltration of TAMs into the TME, which, in turn, also produces CCL2 and amplifies the mobilization of more CCR2+ macrophages to the tumor niche ( 104 – 106 ). Leukemia patients exhibit elevated levels of CCL2 and CXCL12 in the BM and blood, which can critically influence the activation and recruitment of TAMs ( 104 , 107 – 111 ).…”