A Functional Receptor for B-Cell–Activating Factor Is Expressed on Human Acute Lymphoblastic Leukemias

Abstract

B-lineage acute lymphoblastic leukemia (ALL) arises by transformation of a progenitor (pre-B) cell. Cure rates in adults remain low and treatment is complicated by support provided by the microenvironment to the leukemic cells, indicating an urgent need to better understand the factors that promote their survival.

Transcriptional and post-transcriptional mechanisms of BAFF-receptor dysregulation in human B lineage malignancies

“…[11][12][13][14] Although a decrease in CLL patients' circulating BAFF levels damages the hypothesis that BAFF plays a role in tumorigenesis, it is consistent with the malignant cell survival and dampen normal humoral immunity through BAFF-binding. Our studies reported here using precursor B-ALL-derived cell lines support the recently published finding that precursor B cell cancers aberrantly express BAFF-R. 19 These cell lines enabled us to study the mechanisms of expression in a straight-forward way with abundant, manipulatable material.…”

“…1A) are consistent with a recent report demonstrating the presence of BAFF-R on the surface of primary precursor B-ALL cells. 19 We were encouraged to pursue this observation as reflective of a striking and unexpected phenomenon common to B lineage ALL malignancies. This aberrant BAFF-R expression may indeed fuel the growth of these cancers and even play a role in their tumorigenesis, as their normal counterparts entirely lack expression of this anti-apoptotic and costimulatory cytokine receptor.…”

“…Blood was collected from CLL patients after informed consent and Mayo Clinic Institutional Review mechanism of aberrant transcription factor activation, but the complexity of the transcription factor network in these cells and the possibility of epigenetic regulation necessitate significant further investigation. While primary precursor B-ALL cells have been shown to be capable of exploiting soluble BAFF for survival enhancement in vitro, 19 the independence of these cell lines from exogenous BAFF brings the necessity of the receptor into question. However, the possibilities remain that an undetected autocrine BAFF loop is enabling survival, or that a previously active and essential BAFF/BAFF-R axis allowed these cells to escape normal homeostasis during tumorigenesis.…”

“…19 This report encouraged us to pursue the observation that the early B cell lines Reh and NALM-6, derived from patients with precursor B-ALL and proposed to represent malignant clone's reduction of soluble BAFF levels through its active use of BAFF-R. While most evidence supports the active exploitation of a BAFF-mediated survival pathway in CLL and other BAFF-Rexpressing B lineage malignancies, expression of the receptor may significantly dampen normal humoral immunity by acting as a sink for this crucial survival molecule even if the malignancies are entirely divorced from normal BAFF physiology.…”

Diphtheria toxin/human B-Cell activating factor fusion protein kills human acute lymphoblastic leukemia BALL-1 cells: An experimental study

“…Nevertheless, a recent research [9] presented evidence that the BAFF-R is universally expressed on Blineage acute lymphoblastic leukemia (ALL) cells which develop by transformation of normal B-cell progenitors. Other studies have demonstrated that the fusion protein of BAFF and gelonin, a plant toxin, had the killing effects against BAFF-R (+) B lymphoma cells [10,11] .…”