Research Highlights

B cell-specific diversion of glucose carbon utilization reveals a unique vulnerability in B cell malignancies. B-cell activation during normal immune responses and oncogenic transformation impose increased metabolic demands on B-cells and their ability to retain redox homeostasis. While the serine/threonine-protein phosphatase 2A (PP2A) was identified as tumor suppressor in multiple types of cancer, our genetic studies revealed an essential role of PP2A in B-cell tumors. Thereby, PP2A redirects glucose carbon utilization from glycolysis to the pentose phosphate pathway (PPP) to salvage oxidative stress. This unique vulnerability reflects constitutively low PPP activity in B-cells and transcriptional repression of G6PD and other key PPP enzymes by the B-cell transcription factors PAX5 and IKZF1. Reflecting B-cell-specific transcriptional PPP-repression, glucose carbon utilization in B-cells is heavily skewed in favor of glycolysis resulting in lack of PPP-dependent antioxidant protection. These findings reveal a gatekeeper function of the PPP in a broad range of B-cell malignancies that can be efficiently targeted by small molecule inhibition of PP2A and G6PD.
Xiao et al., Cell 173: March 15 (2018)

Metabolic gatekeeper function of B-lymphoid transcription factors.
B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of these transcription factors occur in almost all cases of pre-B ALL. The importance of these lesions in ALL has, until now, remained unclear. Here, by combining ChIP-seq with RNA-seq, we identified a novel B-cell transcriptional program for repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, which prevents malignant transformation. Glucocorticoids are the mainstay of all chemotherapy regimens for B-cell tumors and prevent cellular glucose transport. Our findings provide a mechanistic explanation why glucocorticoids are highly active in energy-deprived B-cell tumors but not in energy-abundant myeloid leukemias.
Chan et al., Nature 542: 479-483 (2017)

PTEN is essential for oncogenic transformation of pre-B cells.
PTEN is a negative regulator of the AKT pathway and a potent tumor suppressor in many types of cancer. In contrast to its role as a tumor suppressor in many types of cancer, loss of one Pten allele in B-cell leukemia caused rapid cell death and was sufficient to induce permanent remission in transplant-recipients. Small-molecule inhibition of PTEN resulted in AKT-hyperactivation and cell death. Loss of PTEN in B-cells was functionally equivalent to autoreactive B-cell receptor signaling, which engaged a deletional checkpoint for the removal of autoreactive B-cells. Targeted inhibition of PTEN and AKT-hyperactivation trigger a checkpoint for elimination of autoreactive B-cells and represent a new strategy to overcome drug resistance.
Shojaee et al., Nature Medicine 22: 379-387 (2016)

Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia.
B-cells of one in 100 neonates carry genetic lesions in their cord blood. Without additional lesions, these clones remain silent and fewer than one in 10,000 such “carriers” will develop leukemia. Our study established that novel interactions between AID and the V(D)J recombinase RAG1 are central in clonal evolution towards leukemia. Repeated inflammatory reactions caused aberrant activation of AID, an enzyme that drives somatic hypermutation of immunoglobulin (Ig) and occasionally, non-Ig genes. Acting together, AID and RAG1 dramatically accelerated clonal evolution towards leukemia. In mice, activating either gene alone only had minor effects. The findings suggest that, by dampening inflammatory responses to infection, vaccines may reduce childhood leukemia risk.
Swaminathan et al., Nature Immunol. 16: 766-774 (2016)

Signaling thresholds and negative B-cell selection in acute lymphoblastic leukemia.
B-cells follow the ‘Goldilocks’ principle of signal strength: if B cell receptor (BCR) signals are either too weak, or too strong as a result of binding to self-antigens, B-cells undergo apoptosis and die. Here we showed that, surprisingly, these mechanisms of B-cell selection remain fully functional in B-cell tumors. Studying patient-derived B-cell tumors, we found that pharmacological hyperactivation of BCR signals reliably triggers autoimmunity checkpoints for elimination of autoreactive B-cells. Compounds to trigger these checkpoints are highly effective, even in B-cell tumors that are fully resistant to conventional chemotherapy.
Chen et al., Nature. 521:357-361 (2015).

Erk negative feedback control enables pre-B cell transformation and represents a therapeutic target in acute lymphoblastic leukemia.
Studying mechanisms of malignant transformation of human B-cells, we found that fluctuations of oncogene signaling strength induced acute cell death. Surviving B-cell clones were selected for strong activation of negative feedback control of Erk signaling. Given the oscillatory behavior of oncogenic tyrosine kinases and RAS oncogenes, we found that B-cells lacking Erk feedback control (e.g. deletion of Dusp6) were protected against malignant transformation. Interestingly, a small molecule inhibitor of DUSP6 selectively induced cell death in patient-derived B-cell leukemia and overcame conventional mechanisms of drug-resistance.
Shojaee et al., Cancer Cell. 28:114-128 (2015)

Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia.
Studying 830 cases from four clinical trials, we found that ALL can be divided into two fundamentally distinct subtypes based on pre-BCR function. While absent in the majority of ALL cases, pre-BCR signaling was found in 13.5%. Pre-BCR signaling induced activation of BCL6, which in turn increased pre-BCR signaling. Inhibition of pre-BCR-related kinases reduced BCL6 expression and selectively killed patient-derived pre-BCR+ ALL cells. These findings identify a genetically and phenotypically distinct ALL subset that critically depends on pre-BCR signaling. In vivo studies suggested that pre-BCR inhibitors are useful for the treatment of patients with pre-BCR+ ALL.
Geng et al., Cancer Cell. 27: 409-425 (2015)

BACH2 mediates negative B cell selection and is a tumor suppressor in B-ALL
Developing B cells that fail to productively rearrange V(D)J segments of immunoglobulin genes are negatively selected, however, the mechanism of apoptosis was unclear. Here, we identified the transcription factor BACH2 as a critical mediator required for clearance of pre-B cell clones that carry non-functional VDJ gene rearrangements. BACH2 opposes the survival factor BCL6 and thereby activates p53, which represents a safeguard against malignant transformation. BACH2 is frequently inactivated in pre-B acute lymphoblastic leukemia (ALL) and deletions of BACH2 predict poor clinical outcome.
Swaminathan et al., Nature Medicine 19: 1014-22 (2013).

BCL6 mediates drug-resistance in B-ALL
B cell-derived acute lymphoblastic leukemia (ALL) is frequently driven by oncogenic tyrosine kinases. Tyrosine kinase inhibitors (TKI) cause initial remission, but relapse occurs within months. This study identified BCL6 as a novel mediator of TKI-resistance. We found that in patient-derived ALL cells, TKI-treatment increased BCL6 protein levels ~90-fold, resulting in transcriptional repression and inactivation of Arf and p53 checkpoint molecules. This induced a stem cell-like state of quiescence and drug-resistance. In animal models, a new BCL6 peptide-inhibitor restored TKI sensitivity and prevented relapse, suggesting a new therapeutic strategy for ALL.
Duy et al., Nature. 485: 384-388 (2012)