The Expression Pattern of the Pre-B Cell Receptor Components Correlates with Cellular Stage and Clinical Outcome in Acute Lymphoblastic Leukemia

Abstract

Precursor-B cell receptor (pre-BCR) signaling represents a crucial checkpoint at the pre-B cell stage. Aberrant pre-BCR signaling is considered as a key factor for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) development. BCP-ALL are believed to be arrested at the pre-BCR checkpoint independent of pre-BCR expression. However, the cellular stage at which BCP-ALL are arrested and whether this relates to expression of the pre-BCR components (IGHM, IGLL1 and VPREB1) is still unclear. Here, we show differential protein expression and copy number variation (CNV) patterns of the pre-BCR components in pediatric BCP-ALL. Moreover, analyzing six BCP-ALL data sets (n = 733), we demonstrate that TCF3-PBX1 ALL express high levels of IGHM, IGLL1 and VPREB1, and are arrested at the pre-B stage. By contrast, ETV6-RUNX1 ALL express low levels of IGHM or VPREB1, and are arrested at the pro-B stage. Irrespective of subtype, ALL with high levels of IGHM, IGLL1 and VPREB1 are arrested at the pre-B stage and correlate with good prognosis in high-risk pediatric BCP-ALL (n = 207). Our findings suggest that BCP-ALL are arrested at different cellular stages, which relates to the expression pattern of the pre-BCR components that could serve as prognostic markers for high-risk pediatric BCP-ALL patients.

Tight regulation of FOXO1 is essential for maintenance of B-cell precursor acute lymphoblastic leukemia

“…7 Pharmacological inactivation of pre-BCR signaling by SYK-or ABL1-inhibitors or overexpression of constitutive active FOXO1 leads to apoptosis. 6 Paradoxically, despite phosphorylation, a substantial proportion of FOXO1 is localized in nuclei 6,7 and apparently activates transcription of direct FOXO targets including RAG1, RAG2, AICDA, and the pre-BCR component VPREB1, which are all essential for leukemogenesis and clonal evolution of BCP-ALL, 7,13,14 contradicting the alleged tumor suppressor role of FOXO1. Importantly, FOXO1 is an essential component of the proliferation and survival program at early stages of B-cell differentiation.…”

Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1 positive pediatric leukemia identifies drug-targetable transcription factor activities

“…These cell state annotations had high agreement also with differentiation state scoring using gene sets defined by flow-sorted B-cell populations ( Fig. 1d) [30]. However, these gene sets defined from bulk transcriptomes scored highly only in the cycling cell states.…”

CD99 expression is strongly associated with clinical outcome in children with B‐cell precursor acute lymphoblastic leukaemia

“…The only TCF3‐PBX1 sample showed CD99 levels similar to pre‐B cells and those in ETV6‐RUNX1 samples were higher than in pre‐B and more similar to pro‐B/CLPs. We have previously shown that these two subtypes appear arrested at the pre‐B and pro‐B stage (Chen et al , ), respectively, which indicates that CD99 expression is a reflection of the cell of origin. Moreover, the six samples with the highest CD99 levels were hyperdiploid, and all six showed CD99 gene amplification (Figure S2), consistent with an additional X ‐chromosome, i.e.…”