While challenges such as incomplete editing efficiency and delivery limitations exist, further optimization may enhance therapeutic efficacy. Overall, our findings demonstrate the efficacy of CRISPR/Cas9 in targeting oncogenic mutations, opening avenues for precision medicine in DLBCL treatment.

2 months ago

Journal

CD79B (CD79b Molecule) • PAX5 (Paired Box 5) • AVEN (Apoptosis And Caspase Activation Inhibitor)

PAX5 mutation

over1year

PAX5 fusion genes in acute lymphoblastic leukemia: A literature review. (PubMed, Medicine (Baltimore))

ELN-PAX5 interaction results in the decreased expression of LEF1, MB1, and BLNK, while PML-PAX5 is critical in the early stages of leukemia. PAX5 fusion genes prevent the transcription of the PAX5 gene, making it an essential target gene for the study of leukemia progression and the diagnosis of B-ALL.

over 1 year ago

Review • Journal

ETV6 (ETS Variant Transcription Factor 6) • PAX5 (Paired Box 5) • FOXP1 (Forkhead Box P1) • LEF1 (Lymphoid Enhancer Binding Factor 1) • BLNK (B Cell Linker)

PAX5 mutation • PAX5 fusion

over1year

Emerging molecular subtypes and therapies in acute lymphoblastic leukemia. (PubMed, Semin Diagn Pathol)

It was classified as early T-precursor lymphoblastic leukemia/lymphoma and T-ALL, NOS in the WHO revised 4th edition and WHO 5th edition. The ICC added an entity into early T-cell precursor ALL, BCL11B-activated, and also added provisional entities subclassified based on transcription factor families that are aberrantly activated.

over 1 year ago

Review • Journal

ABL1 (ABL proto-oncogene 1) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • ETV6 (ETS Variant Transcription Factor 6) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • PAX5 (Paired Box 5) • TCF3 (Transcription Factor 3) • PBX1 (PBX Homeobox 1) • CDX2 (Caudal Type Homeobox 2) • BCL11B (BAF Chromatin Remodeling Complex Subunit BCL11B) • MEF2D (Myocyte Enhancer Factor 2D) • NUTM1 (NUT Midline Carcinoma Family Member 1) • ZEB2 (Zinc Finger E-Box Binding Homeobox 2) • DUX4 (Double Homeobox 4) • ZNF384 (Zinc Finger Protein 384)

KMT2A rearrangement • MLL rearrangement • MYC rearrangement • CRLF2 rearrangement • IKZF1 mutation • PAX5 mutation • ABL1 fusion

almost2years

Protein tyrosine phosphatase Ptpn1 knockout in mouse models drives B-cell hematological malignancies (AACR 2023)

This study demonstrates that Ptpn1 loss along with expression of an NHD13 fusion gene leads to a highly penetrant BCP ALL in mice, suggesting a role for Ptpn1 in preventing malignant transformation. Taken together, these findings are consistent with a collaborative model for BCP ALL in which the NHD13 transgene leads to increased stem cell self-renewal, somatic Bcor or Pax5 mutations block normal B cell differentiation, and somatic signaling mutations (Jak1/3, Flt3) lead to hyperproliferation, which is potentiated by Ptpn1 deficiency.

almost 2 years ago

Preclinical

FLT3 (Fms-related tyrosine kinase 3) • CD19 (CD19 Molecule) • BCOR (BCL6 Corepressor) • JAK1 (Janus Kinase 1) • PAX5 (Paired Box 5) • NUP98 (Nucleoporin 98 And 96 Precursor 2) • JAK3 (Janus Kinase 3) • PTPN1 (Protein Tyrosine Phosphatase Non-Receptor Type 1) • MCM2 (Minichromosome maintenance complex component 2)

CD19 expression • JAK3 mutation • PAX5 mutation

2years

Unmatched Whole-Genome Sequencing As a Clinical Tool for Hematological Neoplasms with Significant Utility in Cases with Tumor-in-Normal Contamination (ASH 2022)

Conclusions We have developed and validated an uWGS workflow for the detection of clinically relevant alterations in leukemia across variant classes to include CNVs, translocations and point mutations. We demonstrated that for hematological neoplasms, uWGS rescues events that can be missed by mWGS workflows owing to TiN, which shows how uWGS enables the detection of clinically relevant biomarkers, and the opportunity to discover new clinical findings using a single test and a single biopsy.

2 years ago

Clinical

CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NOTCH1 (Notch 1) • NF1 (Neurofibromin 1) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • CHEK2 (Checkpoint kinase 2) • JAK1 (Janus Kinase 1) • PAX5 (Paired Box 5) • EP300 (E1A binding protein p300) • TCF3 (Transcription Factor 3) • P2RY8 (P2Y Receptor Family Member 8) • ZEB2 (Zinc Finger E-Box Binding Homeobox 2) • ZNF384 (Zinc Finger Protein 384)

CDKN2A deletion • NF1 deletion • PAX5 mutation

over2years

GENOMIC CHARACTERISATION OF B-OTHER ALL IN UKALL2003 PATIENTS BY NEXT GENERATION SEQUENCING (EHA 2022)

The identification of DUX4 -r, subgroup defining mutations and fusion partner genes demonstrates the value of NGS-based approaches. We have confirmed the good and poor prognostic associations of DUX4 -r and ABL-class fusions, respectively, and identified ETV6-RUNX1 -like subgroup to have a good prognosis.

over 2 years ago

Clinical • Next-generation sequencing

RUNX1 (RUNX Family Transcription Factor 1) • ETV6 (ETS Variant Transcription Factor 6) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • PAX5 (Paired Box 5) • ZEB2 (Zinc Finger E-Box Binding Homeobox 2)

CRLF2 rearrangement • PAX5 mutation • PAX5 fusion

over2years

PAX5 DEFICIENCY AND GERMLINE SUSCEPTIBILITY TO PEDIATRIC LEUKEMIA (EHA 2022)

Ultimately these characterizations will help to advance the understanding of molecular mechanisms and susceptible populations associated with B-ALL. In turn, these findings are important to address the far more frequent somatic PAX5 mutations with the goal to prevent or treat a significant proportion of childhood leukemias.

over 2 years ago

Clinical

CD19 (CD19 Molecule) • PAX5 (Paired Box 5) • IL2RA (Interleukin 2 receptor, alpha) • LYN (LYN Proto-Oncogene Src Family Tyrosine Kinase) • CD79A (CD79a Molecule)

PAX5 mutation

3years

PAX5 haploinsufficiency induces low T cell infiltration in the cancer microenvironment via reduced chemokines. (PubMed, Curr Mol Med)

Our study showed that PAX5 haploinsufficiency induced low T cell infiltration in TME using decreased chemokines.

3 years ago

Journal

CD8 (cluster of differentiation 8) • CXCL10 (Chemokine (C-X-C motif) ligand 10) • PAX5 (Paired Box 5) • CXCL9 (Chemokine (C-X-C motif) ligand 9) • CD4 (CD4 Molecule) • CCL2 (Chemokine (C-C motif) ligand 2)

PAX5 mutation • PAX5 deletion

3years

Alisertib Synergistically Strengthens the Anti-Leukemia Activity of Venetoclax in TCF3-Hlf B-ALL (ASH 2021)

We identified AURKA as a critical new driver in TCF3-HLF ALL via orthogonal genetic and functional assays and confirmed prior observations of BCL-2 dependency in our models. We validated these key targets via in vitro and in vivo pharmacologic inhibition studies with drug synergy detected with combined alisertib and venetoclax in human TCF3-HLF ALL cell lines and PDX models. We posit that dual AURKA and BCL-2 inhibition is a clinically-pragmatic and potentially effective therapeutic strategy for patients with this rare, but highly fatal, leukemia subtype that merits formal clinical investigation.

3 years ago

IO biomarker

CD19 (CD19 Molecule) • CD22 (CD22 Molecule) • PAX5 (Paired Box 5) • TCF3 (Transcription Factor 3) • AURKB (Aurora Kinase B)

PAX5 mutation

Venclexta (venetoclax) • alisertib (MLN8237)

3years

Forward and Reverse Genetics of B Cell Malignancies: From Insertional Mutagenesis to CRISPR-Cas. (PubMed, Front Immunol)

We also discuss reverse genetic models and screens that use CRISPR-Cas, ORFs and shRNAs to provide high throughput in vivo proof of oncogenic function, with an emphasis on models using adoptive transfer of ex vivo cultured cells. Finally, we summarize mouse models that offer temporal regulation of candidate genes in an in vivo setting to demonstrate the potential of their encoded proteins as therapeutic targets.

3 years ago

Review • Journal

PAX5 (Paired Box 5)

PAX5 mutation

over3years

PAX5 haploinsufficiency induced CD8+ T cells dysfunction or exhaustion by high expression of immune inhibitory-related molecules. (PubMed, Cancer Treat Res Commun)

Our study showed that PAX5 haploinsufficiency induced CD8+ T cells dysfunction or exhaustion by high expression of TIM3, NR4A1 and BATF in the CD8+ T cells of TME.

over 3 years ago

Journal

CD8 (cluster of differentiation 8) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • PAX5 (Paired Box 5)

HAVCR2 expression • PAX5 mutation • PAX5 deletion

over3years

[VIRTUAL] IL7R MUTATIONAL ACTIVATION CAN INITIATE PH-LIKE AND PAX5 P80R PRECURSOR B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (EHA 2021)

Because IL7R mutant leukemias exhibit clear upregulation of mTOR signaling, we administered the clinical-grade dual PI3K and mTOR inhibitor dactolisib and show it has a striking impact on the frequency of leukemia cells in the blood, significantly prolonging mouse survival...Importantly, we validated our findings in IL7R mutant primary human B-ALLs. Conclusion Our studies provide a novel, powerful in vivo resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, and demonstrate for the first time that IL7R can initiate this malignancy.

over 3 years ago

IO biomarker

KRAS (KRAS proto-oncogene GTPase) • BCL2 (B-cell CLL/lymphoma 2) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • IKZF1 (IKAROS Family Zinc Finger 1) • JAK1 (Janus Kinase 1) • PAX5 (Paired Box 5) • IL7R (Interleukin 7 Receptor) • ARID2 (AT-Rich Interaction Domain 2)

KRAS mutation • CDKN2A deletion • CDKN2A mutation • IL7R mutation • PAX5 mutation • KRAS deletion

dactolisib (RTB101)

almost4years

Identification of novel, clonally stable, somatic mutations targeting transcription factors PAX5 and NKX2-3, the epigenetic regulator LRIF1, and BRAF in a case of atypical B-cell chronic lymphocytic leukemia harboring a t(14;18)(q32;q21). (PubMed, Cold Spring Harb Mol Case Stud)

This is suggestive of a role for these novel mutations in B-CLL initiation and stable clonal evolution, including upon treatment withdrawal. This case extends the spectrum of atypical B-CLL with t(14;18)(q32;q21) and highlights the value of more global precision genomics for patient follow-up and treatment in these patients.

almost 4 years ago

Clinical • Journal • IO biomarker

BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • NOTCH1 (Notch 1) • PAX5 (Paired Box 5) • NKX2-3 (NK2 Homeobox 3)

TP53 mutation • BRAF mutation • PAX5 mutation

almost4years

Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia. (PubMed, Front Med)

Multiagent therapy regimens, including target inhibitors (e.g., imatinib), immunomodulators, monoclonal antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy, are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management. We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.

almost 4 years ago

Review • Journal • IO biomarker

BCL2 (B-cell CLL/lymphoma 2) • RUNX1 (RUNX Family Transcription Factor 1) • BCL6 (B-cell CLL/lymphoma 6) • ETV6 (ETS Variant Transcription Factor 6) • IKZF1 (IKAROS Family Zinc Finger 1) • PAX5 (Paired Box 5) • MEF2D (Myocyte Enhancer Factor 2D)

BCL6 rearrangement • BCL2 rearrangement • PAX5 mutation

imatinib

4years

Inhibition of inflammatory signaling in Pax5 mutant cells mitigates B-cell leukemogenesis. (PubMed, Sci Rep)

Additionally, this novel IL-6 signaling paradigm identified in mice was also substantiated in humans. Altogether, our studies establish aberrant IL6 expression caused by Pax5 loss as a hallmark of Pax5-dependent B-ALL and the IL6 as a therapeutic vulnerability for B-ALL characterized by PAX5 loss.

4 years ago

Journal

IL6 (Interleukin 6) • PAX5 (Paired Box 5)

PAX5 mutation

4years

[VIRTUAL] Frequency and Prognostic Significance of Recurrent Gene Mutations in Pediatric B-ALL: Report from the DFCI ALL Consortium (ASH 2020)

Future trials may integrate these findings into risk stratification of HHD ALL. With prospective continued clinical use of NGS assays, we will further clarify the role of mutations and their contribution to disease outcomes in B-ALL.

4 years ago

Clinical

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • JAK2 (Janus kinase 2) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • RUNX1 (RUNX Family Transcription Factor 1) • ETV6 (ETS Variant Transcription Factor 6) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • CRLF2 (Cytokine Receptor Like Factor 2) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • TSC2 (TSC complex subunit 2) • CREBBP (CREB binding protein) • PAX5 (Paired Box 5) • TSC1 (TSC complex subunit 1) • PIK3R1 (Phosphoinositide-3-Kinase Regulatory Subunit 1) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • PIK3CB (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) • JAK3 (Janus Kinase 3) • CCND3 (Cyclin D3) • SOCS1 (Suppressor Of Cytokine Signaling 1) • SH2B3 (SH2B Adaptor Protein 3)

TP53 mutation • KRAS mutation • FLT3 mutation • MLL rearrangement • TSC1 mutation • JAK3 mutation • PAX5 mutation • SETD2 mutation

4years

Germline PAX5 mutation predisposes to familial B acute lymphoblastic leukemia. (PubMed, Blood)

Our data highlight the importance of transcriptional deregulation, particularly of genes involved in B cell differentiation in familial BCP-ALL. We demonstrated that inherited genetic basis of susceptibility to BCP-ALL has been underestimated and should be considered before any familial allograft.

4 years ago

Journal

PAX5 (Paired Box 5)

PAX5 mutation

4years

EBF1 and Pax5 safeguard leukemic transformation by limiting IL-7 signaling, Myc expression, and folate metabolism. (PubMed, Genes Dev)

We show that blockade of IL-7 signaling in vivo and methotrexate treatment of leukemic cells in vitro attenuate the expansion of leukemic cells. Single-cell RNA-sequencing revealed heterogeneity of leukemic cells and identified a subset of wild-type pro-B cells with reduced Ebf1 and enhanced Myc expression that show hallmarks of dHet B-ALL cells. Thus, EBF1 and Pax5 may safeguard early stage B cells from transformation to B-ALL by limiting IL-7 signaling, folate metabolism and Myc expression.

4 years ago

Journal

MYC (V-myc avian myelocytomatosis viral oncogene homolog) • PAX5 (Paired Box 5) • EBF1 (EBF Transcription Factor 1)

MYC expression • PAX5 mutation

methotrexate