Bone Marrow Cells in Acute Lymphoblastic Leukemia Create a Proinflammatory Microenvironment Influencing Normal Hematopoietic Differentiation Fates

Abstract

B-cell acute lymphoblastic leukemia (B-ALL) is a serious public health problem in the pediatric population worldwide, contributing to 85% of deaths from childhood cancers. Understanding the biology of the disease is crucial for its clinical management and the development of therapeutic strategies. In line with that observed in other malignancies, chronic inflammation may contribute to a tumor microenvironment resulting in the damage of normal processes, concomitant to development and maintenance of neoplastic cells. We report here that hematopoietic cells from bone marrow B-ALL have the ability to produce proinflammatory and growth factors, including TNFα, IL-1β, IL-12, and GM-CSF that stimulate proliferation and differentiation of normal stem and progenitor cells. Our findings suggest an apparently distinct CD13+CD33+ population of leukemic cells contributing to a proinflammatory microenvironment that may be detrimental to long-term normal hematopoiesis within B-ALL bone marrow.

Pro-inflammatory-Related Loss of CXCL12 Niche Promotes Acute Lymphoblastic Leukemic Progression at the Expense of Normal Lymphopoiesis

“…Remarkably, the cellular communication between leukemic cells and MSC through exosomes or across nanotubes (65, 66) and the disruption of the CXCR4/CXCL12 axis (28, 59), suggesting a key role for G-CSF in this phenomena, are consistent with our previous reports about production of pro-inflammatory factors by tumor cells (30), related to G-CSF and Gfi-1 (29). Accordingly, G-CSF administration in a preclinical model of ALL showed an increased tumor burden (67), and its mechanism may be operating in the niche because B cell malignances rarely expressed G-CSF receptor and are unable to respond in vitro to this cytokine (68).…”

“…Accordingly, previous work in our lab suggests an important damage in the frequency and function of hematopoietic stem and progenitor cells (HSPC) in the BM of ALL patients accompanied by an abnormal and pro-inflammatory secretion profile (e.g., increased secretion of IL-1β and TNFα) (29, 30). In order to address the molecular pathways involved in hematopoietic and microenvironmental alterations that may favor disease progression, we recently constructed a Boolean model, which demonstrates that constitutive activation of NF-κB in the hematopoietic molecular network was sufficient to establish a positive feedback loop that maintain the constitutive secretion of pro-inflammatory cytokines (e.g., IL-1β and G-CSF) and induce the disruption of the CXCR4/CXCL12 axis, which is crucial for the maintenance of the hematopoietic cells in their regulatory niche.…”

Pediatric precursor B acute lymphoblastic leukemia: are T helper cells the missing link in the infectious etiology theory?

“…More recently, a proliferative effect of the cytokines IL-17 and IL-21 on BCP-ALL cells has been reported [85]. The observations that cytokines may be involved in the pathogenesis of BCP-ALL are consistent with the highly inflammatory environment in the bone marrow of leukemia patients [40]. …”

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

“…35–37 Other blinatumomab binding-associated parameters (e.g., KD CD3, KD receptor_CD19 ) and compound and reaction system-associated parameters (e.g., EC 50 , γ, τ reference , k τ1, k τ2 ) were assumed to be the same for in vitro and in vivo conditions. Since immune suppression is expected in patients with ALL, which may be associated with both upregulation of regulatory T cells and altered levels of cytokines, 38–40 k max for T cells from patients with relapsed or refractory ALL was assumed to be 1/3 of that from healthy T cells clone (0.0693 1/hr). Tumor doubling time in patients with ALL was assumed to be 33 days based on literature report, 20 and the derived k g was 0.00126 1/hr.…”