Aberrant Notch Signaling in the Bone Marrow Microenvironment of Acute Lymphoid Leukemia Suppresses Osteoblast-Mediated Support of Hematopoietic Niche Function

Abstract

More than half of T-ALL patients harbor gain-of-function mutations in the intracellular domain of Notch1. Diffuse infiltration of the bone marrow commonly occurs in T-ALL and relapsed B-ALL patients, and is associated with worse prognosis. However, the mechanism of leukemia outgrowth in the marrow and the resulting biological impact on hematopoiesis are poorly understood. Here, we investigated targetable cellular and molecular abnormalities in leukemia marrow stroma responsible for the suppression of normal hematopoiesis using a T-ALL mouse model and human T-ALL xenografts. We found that actively proliferating leukemia cells inhibited normal hematopoietic stem and progenitor cell (HSPC) proliferation and homing to the peri-vascular region. In addition, leukemia development was accompanied by the suppression of the endosteum-lining osteoblast population. We further demonstrate that aberrant Notch activation in the stroma plays an important role in negatively regulating the expression of CXLC12 on osteoblasts and their differentiation. Notch blockade reversed attenuated HSPC cycling, leukemia-associated abnormal blood lineage distribution and thrombocytopenia as well as recovered osteoblast and HSPC abundance and improved the hematopoietic-supportive functions of osteoblasts. Finally, we confirmed that reduced osteoblast frequency and enhanced Notch signaling were also features of the marrow stroma of human ALL tissues. Collectively, our findings suggest that therapeutically targeting the leukemia-infiltrated hematopoietic niche may restore HSPC homeostasis and improve the outcome of ALL patients.

The mazy case of Notch and immunoregulatory cells

“…The use of conditioned medium prepared from ex vivo cultures of N1ICD-transplanted bone marrow was sufficient to reproduce the process, arguing that tumor cells may act through secreting soluble factors [71]. Recently, with the use of the same model of Notch-dependent T-ALL, Wang and collaborators [72] reported that N1ICD leukemic cells in the bone marrow microenvironment induced both the suppression of the endosteal/osteoblast niche and the alteration of the perivascular region, thus impairing proliferation and homing of HSC progenitors. Besides, the authors described a progressive expansion of Gr1 + myeloid cells in a nontransformed compartment, mainly influenced by tumor cells, through an induced activation of Notch signaling in the bone marrow stroma.…”

“…Besides, the authors described a progressive expansion of Gr1 + myeloid cells in a nontransformed compartment, mainly influenced by tumor cells, through an induced activation of Notch signaling in the bone marrow stroma. This led to the up-regulated expression of inflammatory cytokines, such as IL-6 [72]. IL-6 represents one of the most important factors determining expansion and activation of MDSCs, following the so-called "2-signal" theory of their differentiation [73].…”

The bone marrow microenvironment—driver of leukemia evolution?

“…Moreover, treatment of AML mice with compounds that inhibit osteoblast loss increased survival (14). In T-cell acute lymphoblastic leukemia (T-ALL) Notch overexpression suppressed osteoblast differentiation (16). In contrast, in a myeloproliferative neoplasia (MPN) mouse model an increase in trabecular number and thickness was observed and functional osteoblast were replaced by altered osteoblast that overproduced pro-inflammatory cytokines and myeloid differentiation signals (17).…”

A Sanctuary for cancer cells: Microenvironment in T-cell acute lymphoblastic leukemia survival and drug resistance

“…Using four-dimensional imaging, Hawkins et al pointed out how T-ALL cells invade the bone marrow and lead to rapid remodeling of the endosteal niche, with a total loss of mature osteoblasts. Similarly, using a mouse model of Notch-driven T-ALL, Wang et al [32] showed that leukemic cells affect the homing of healthy HSCs, compete for the occupancy of perivascular areas and suppress the number of osteoblasts, disrupting the normal hematopoiesis. The authors demonstrated the key role of Notch pathway in these processes, since Notch blockade recovered the osteoblasts and fostered HSCs proliferation in vivo.…”