scholarly journals Single cell mRNA signals reveal a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia

2021 ◽  
Author(s):  
Eleonora Khabirova ◽  
Laura Jardine ◽  
Tim Coorens ◽  
Simone Webb ◽  
Taryn Treger ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Meta Analysis ◽  
Developmental State ◽  
Gene Fusions ◽  
The Core ◽  
Increasing Trend ◽  
Cell Acute Lymphoblastic Leukemia

Infant B-cell acute lymphoblastic leukemia (B-ALL) has not followed the increasing trend towards cure seen in other childhood B-ALLs. The prognosis for infants with KMT2A gene fusions is especially poor, and the origins of this aggressive leukemia remain unknown. Here, we investigated the developmental state of KMT2A-rearranged infant B-ALL within hematopoietic hierarchies of human fetal bone marrow, using bulk mRNA meta-analysis of childhood leukemia and examination of single lymphoblast transcriptomes. KMT2A-rearranged infant B-ALL was uniquely dominated by an early lymphocyte precursor (ELP) state. Direct comparison of infant lymphoblasts with ELP cells distilled the core oncogenic transcriptome of cancer cells which harboured potentially targetable hybrid myeloid-lymphoid features. Overall our quantitative molecular analyses demonstrate a distinct developmental state of KMT2A-rearranged infant B-ALL.

scholarly journals Outcome of children with multiply relapsed B-cell acute lymphoblastic leukemia: a therapeutic advances in childhood leukemia & lymphoma study

Leukemia ◽  
2018 ◽  
Vol 32 (11) ◽  
pp. 2316-2325 ◽  
Author(s):  
Weili Sun ◽  
Jemily Malvar ◽  
Richard Sposto ◽  
Anupam Verma ◽  
Jennifer J. Wilkes ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1

2022 ◽  
Author(s):  
Adria Closa ◽  
Marina Reixachs-Solé ◽  
Antonio Fuentes-Fayos ◽  
Katharina Hayer ◽  
Juan Melero ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Protein Interactions ◽  
Lymphoblastic Leukemia ◽  
Significant Proportion ◽  
Splicing Factor ◽  
Gene Fusions ◽  
Malignant Phenotype ◽  
Dismal Prognosis ◽  
Cell Acute Lymphoblastic Leukemia

Abstract A significant proportion of B-cell acute lymphoblastic leukemia (B-ALL) patients remains with a dismal prognosis due to yet undetermined mechanisms. We performed a comprehensive multicohort analysis of gene fusions, gene expression, and RNA splicing alterations to uncover molecular signatures potentially linked to the observed poor outcome. We identified 84 fusions with significant allele frequency across patients. We identified an expression signature that predicts high risk independently of the gene fusion background. This signature includes the upregulation of the splicing factor SRRM1, which potentially impacts splicing events associated with poor outcomes through protein-protein interactions with other splicing factors. Experiments in B-ALL cell lines provided further evidence for the role of SRRM1 on cell survival, proliferation, and invasion. Our findings reveal a convergent mechanism of aberrant RNA processing that sustains a malignant phenotype independently of gene fusions and could complement current clinical strategies in B-ALL.

scholarly journals A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1

2021 ◽  
Author(s):  
Adria Closa ◽  
Marina Reixachs-Sole ◽  
Antonio C Fuentes-Fayos ◽  
Katharina E Hayer ◽  
Juan L Melero ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Protein Interactions ◽  
Lymphoblastic Leukemia ◽  
Significant Proportion ◽  
Splicing Factor ◽  
Gene Fusions ◽  
Malignant Phenotype ◽  
Dismal Prognosis ◽  
Cell Acute Lymphoblastic Leukemia

A significant proportion of B-cell acute lymphoblastic leukemia (B-ALL) patients remains with a dismal prognosis due to yet undetermined mechanisms. We performed a comprehensive multicohort analysis of gene fusions, gene expression, and RNA splicing alterations to uncover molecular signatures potentially linked to the observed poor outcome. We identified 84 fusions with significant allele frequency across patients. We identified an expression signature that predicts high risk independently of the gene fusion background. This signature includes the upregulation of the splicing factor SRRM1, which potentially impacts splicing events associated with poor outcomes through protein-protein interactions with other splicing factors. Experiments in B-ALL cell lines provided further evidence for the role of SRRM1 on cell survival, proliferation, and invasion. Our findings reveal a convergent mechanism of aberrant RNA processing that sustains a malignant phenotype independently of gene fusions and could complement current clinical strategies in B-ALL.

scholarly journals Siglec-15 Is a Novel Immunomodulatory Protein and Therapeutic Target in Childhood Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-7
Author(s):  
Claire E. Pillsbury ◽  
Jairo A. Fonseca ◽  
Jodi Dougan ◽  
Hasan Abukharma ◽  
Linda N. Liu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Healthy Donor ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Myelogenous Leukemia ◽  
Soluble Form ◽  
Pediatric Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

Despite advances that have greatly improved the overall survival of pediatric B cell acute lymphoblastic leukemia (B-ALL), it remains one of the leading causes of cancer-related death in children. Immunotherapy has shown efficacy in treatment of refractory disease, highlighting the need for greater understanding of the immune evasion mechanisms underlying this disease so that additional immune modulating therapeutic strategies can be developed. Siglec-15 (Sig15) was recently reported to have immune modulatory functions in the context of solid tumors. We have found that SIGLEC15 is overexpressed at the RNA level in primary B cell acute lymphoblastic leukemia (B-ALL), acute myelogenous leukemia (AML), and diffuse large B cell lymphoma as compared to healthy donor controls. As compared to healthy donor PBMCs, we have confirmed higher expression of Sig15 at the RNA and protein levels through RT-qPCR, immunoblotting, and flow cytometry across a panel of human B-ALL, AML, DLBCL, and T cell acute lymphoblastic leukemia (T-ALL) cell lines. Knockout of Sig15 expression in a BCR-ABL1+ murine model of B-ALL engrafted in immunocompetent and Rag1-/- immunodeficient recipients resulted in leukemia clearance in immunocompetent, but not immunodeficient, recipients and 100% survival (Figure 1). These data suggest a prominent role for Sig15 in the suppression of adaptive immune response to B-ALL as well as other hematological malignancies. Additional studies suggest that SIGLEC15 expression is positively regulated by NFκB signaling, which is known to be constitutively activated in certain B-ALL subsets. Importantly, we have observed release of a soluble form of Sig15 (sSig15) from B-ALL cells, which is regulated by PKC and calcineurin-mediated signaling. To discover translational application, we measured sSig15 in the plasma of both healthy and pediatric leukemia patients and found significantly higher levels of sSig15 as compared to healthy individuals (Figure 2; LLD = 5 pg/ml; **P<0.01). Together, these results suggest Siglec-15 is a novel and potent immunosuppressive molecule active in leukemia that may be targeted therapeutically to activate lymphocytes against leukemia cells. Disclosures Abukharma: NextCure, Inc.: Current Employment. Liu:NextCure, Inc.: Current Employment.

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