Targeting the TNF/IAP pathway synergizes with anti-CD3 immunotherapy in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Current treatments, based on intensive chemotherapy regimens provide overall survival rates of ∼85% in children and <50% in adults, calling the search of new therapeutic options. We previously reported that targeting the T-cell receptor (TCR) in T-ALL with anti-CD3 (αCD3) monoclonal antibodies (mAbs) enforces a molecular program akin to thymic negative selection, a major developmental checkpoint in normal T-cell development; induces leukemic cell death; and impairs leukemia progression to ultimately improve host survival.

NFAT transcription factors are essential and redundant actors for leukemia initiating potential in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy with few available targeted therapies. We previously reported that the phosphatase calcineurin (Cn) is required for LIC (leukemia Initiating Capacity) potential of T-ALL pointing to Cn as an interesting therapeutic target. Calcineurin inhibitors have however unwanted side effect.

AXL Inhibition in Macrophages Stimulates Host-versus-Leukemia Immunity and Eradicates Naïve and Treatment-Resistant Leukemia.

Acute leukemias are systemic malignancies associated with a dire outcome. Because of low immunogenicity, leukemias display a remarkable ability to evade immune control and are often resistant to checkpoint blockade. Here, we discover that leukemia cells actively establish a suppressive environment to prevent immune attacks by co-opting a signaling axis that skews macrophages toward a tumor-promoting tissue repair phenotype, namely the GAS6/AXL axis.

Epigenetic analysis of patients with T-ALL identifies poor outcomes and a hypomethylating agent-responsive subgroup.

Adult "T cell" acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that is associated with poor outcomes, requiring additional therapeutic options. The DNA methylation landscapes of adult T-ALL remain undercharacterized. Here, we systematically analyzed the DNA methylation profiles of normal thymic-sorted T cell subpopulations and 143 primary adult T-ALLs as part of the French GRAALL 2003-2005 trial.

Preclinical efficacy of humanized, non-FcγR-binding anti-CD3 antibodies in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that accounts for ∼20% of ALL cases. Intensive chemotherapy regimens result in cure rates >85% in children and <50% in adults, warranting a search of novel therapeutic strategies. Although immune-based therapies have tremendously improved the treatment of B-ALL and other B-cell malignancies, they are not yet available for T-ALL.

The TCR/CD3 complex in leukemogenesis and as a therapeutic target in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) arises from T cell precursors and is characterized by expression of many lineage-specific proteins. While T-cell antigen receptor (TCR) signaling and its strength are central for thymocyte development, mature T cell homeostasis and immune responses, their roles in T-ALL remain undetermined. Indeed, in contrast to mouse models, in which absence of TCR or major histocompatibility complex binding does not impact on leukemogenesis, other mouse models suggest that basal or weak signaling drives leukemia development.

Novel Intergenically Spliced Chimera, , Is Associated with Aggressive T-ALL Biology and Outcome.

Leukemias are frequently characterized by the expression of oncogenic fusion chimeras that normally arise due to chromosomal rearrangements. Intergenically spliced chimeric RNAs (ISC) are transcribed in the absence of structural genomic changes, and aberrant ISC expression is now recognized as a potential driver of cancer. To better understand these potential oncogenic drivers, high-throughput RNA sequencing was performed on T-acute lymphoblastic leukemia (T-ALL) patient specimens ( = 24), and candidate T-ALL-related ISCs were identified ( = 55; a median of 4/patient).

Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia.

Unlabelled: Cancer onset and progression involves the accumulation of multiple oncogenic hits, which are thought to dominate or bypass the physiologic regulatory mechanisms in tissue development and homeostasis. We demonstrate in T-cell acute lymphoblastic leukemia (T-ALL) that, irrespective of the complex oncogenic abnormalities underlying tumor progression, experimentally induced, persistent T-cell receptor (TCR) signaling has antileukemic properties and enforces a molecular program resembling thymic negative selection, a major developmental event in normal T-cell development. Using mouse models of T-ALL, we show that induction of TCR signaling by high-affinity self-peptide/MHC or treatment with monoclonal antibodies to the CD3ε chain (anti-CD3) causes massive leukemic cell death.

Microenvironmental cues for T-cell acute lymphoblastic leukemia development.

Intensive chemotherapy regimens have led to a substantial improvement in the cure rate of patients suffering from T-cell acute lymphoblastic leukemia (T-ALL). Despite this progress, about 15% and 50% of pediatric and adult cases, respectively, show resistance to treatment or relapse with dismal prognosis, calling for further therapeutic investigations. T-ALL is an heterogeneous disease, which presents intrinsic alterations leading to aberrant expression of transcription factors normally involved in hematopoietic stem/progenitor cell development and mutations in genes implicated in the regulation of cell cycle progression, apoptosis, and T-cell development.

CXCR4 Is Required for Leukemia-Initiating Cell Activity in T Cell Acute Lymphoblastic Leukemia.

Impaired cell migration has been demonstrated in T cell acute lymphoblastic leukemia (T-ALL) cells upon calcineurin inactivation, among other phenotypic traits including increased apoptosis, inhibition of cell proliferation, and ultimately inhibition of leukemia-initiating cell (LIC) activity. Herein we demonstrate that the chemokine receptor CXCR4 is essential to the LIC activity of T-ALL leukemic cells both in NOTCH-induced mouse T-ALL and human T-ALL xenograft models. We further demonstrate that calcineurin regulates CXCR4 cell-surface expression in a cortactin-dependent manner, a mechanism essential to the migratory properties of T-ALL cells.

ISG15 modulates development of the erythroid lineage.

Activation of erythropoietin receptor allows erythroblasts to generate erythrocytes. In a search for genes that are up-regulated during this differentiation process, we have identified ISG15 as being induced during late erythroid differentiation. ISG15 belongs to the ubiquitin-like protein family and is covalently linked to target proteins by the enzymes of the ISGylation machinery.

Erythroblast transformation by FLI-1 depends upon its specific DNA binding and transcriptional activation properties.

FLI-1 is a transcriptional regulator of the ETS family of proteins. Insertional activation at the FLI-1 locus is an early event in F-murine leukemia virus-induced erythroleukemia. Consistent with its essential role in erythroid transformation, enforced expression of FLI-1 in primary erythroblasts strongly impairs the response of these cells to erythropoietin (Epo), a cytokine essential to erythropoiesis.

Up-regulation of SLAP in FLI-1-transformed erythroblasts interferes with EpoR signaling.

Rearrangement of the FLI-1 locus and ensuing overexpression of FLI-1 protein is an early event in Friend murine leukemia virus (F-MuLV)-induced erythroleukemia. When overexpressed in primary erythroblasts, FLI-1 converts erythropoietin (Epo)-induced terminal differentiation into a proliferative response. We found that SLAP, a gene encoding a recently described negative regulator of T-cell antigen receptor function during thymocyte development, is up-regulated both at the RNA and protein levels in FLI-1-transformed erythroblasts.

Direct regulation of BCL-2 by FLI-1 is involved in the survival of FLI-1-transformed erythroblasts.

Rearrangement of the FLI-1 locus with ensuing overexpression of FLI-1 is an early event in Friend murine leukemia virus-induced disease. When overexpressed in primary erythroblasts, FLI-1 blocks erythropoeitin (Epo)-induced terminal differentiation and inhibits apoptosis normally induced in response to Epo withdrawal. We show here that the survival-inducing property of FLI-1 is associated with increased transcription of BCL-2.