TCF3 gene rearrangements in pediatric B‐cell acute lymphoblastic leukemia—A single center experience

Abstract

Introduction: B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common neoplasm in children. One of the long known recurrent rearrangements in BCP-ALL is t(1;19)(q23;p13.3)/TCF3::PBX1. However, other TCF3 gene rearrangements were also described that are associated with significant difference in ALL prognosis. Methods:The current study aimed to analyze the spectrum of TCF3 gene rearrangements in children in Russian Federation. A cohort of 203 patients with BCP-ALL was selected based on FISH screening and was studied by karyotyping, FISH, RT-PCR and high throughput sequencing.Results: T(1;19)(q23;p13.3)/TCF3::PBX1 is the most common aberration in TCF3positive pediatric BCP-ALL (87.7%), with its unbalanced form prevailing. It resulted from TCF3::PBX1 exon 16-exon 3 fusion junction (86.2%) or unconventional exon 16-exon 4 junction (1.5%). Rarer events included t(12;19)(p13;p13.3)/TCF3::ZNF384 (6.4%) and t(17;19)(q21-q22;p13.3)/TCF3::HLF (1.5%). The latter translocations demonstrated high molecular heterogeneity and complex structure-four distinct transcripts were shown for TCF3::ZNF384 and each patient with TCF3::HLF had a unique transcript. These features hamper TCF3 rearrangement primary detection by molecular methods and brings FISH screening to the fore. A case of novel TCF3::TLX1 fusion in a patient with t(10;19)(q24;p13) was also discovered. Survival analysis within the national pediatric ALL treatment protocol demonstrated the severe prognosis of TCF3::HLF compared to both TCF3::PBX1 and TCF3::ZNF384. Conclusion:So, high molecular heterogeneity of TCF3 gene rearrangement in pediatric BCP-ALL was demonstrated and a novel fusion gene TCF3::TLX1 was described.

Leukemogenesis in Acute Lymphoblastic Leukemia through the Lens of Developmental Dynamics of Lymphoid Progenitor Cells: a systematic review

“…Dysregulation of E2A (TCF3) can lead to the development of Acute Lymphoblastic Leukemia (ALL) by altering downstream genes, transcription factors (TFs), and signaling pathways critical for normal lymphoid development. E2A regulates the expression of genes involved in lymphoid lineage commitment, differentiation, and cell cycle control [61]. Dysregulated E2A activity may result in aberrant expression of downstream genes crucial for lymphoid development, favoring leukemogenesis by promoting proliferation, survival, and self-renewal while suppressing differentiation and apoptosis-related genes.…”

Biological Markers of High-Risk Childhood Acute Lymphoblastic Leukemia

“…Survival data and available targeted therapies for patients with high-risk ALL are summarized in Table 1. TKIs, JAK inhibitors (ruxolitinib) [15,16] KMT2A rearranged 6-year EFS 73.9% (infants) [17] 6-year OS 87.2% (infants) [17] Blinatumomab, CAR T-cells [18], menin inhibitors [19] MEF2D rearranged 74% (63-82%) (children and adolescents 1-18 years) [20] 81% (71-88%) (children and adolescents 1-18 years) [20] HDAC inhibitors [21], proteasome inhibitors [22] TCF3::HLF fusion 25 ± 21.7% (infants, children, and adolescents 0-18 years) [23] 37.5 ± 28.6% (infants, children, and adolescents 0-18 years) [23] BCL2 inhibitors [24], PARP inhibitors [25], blinatumomab followed by HSCT [ 93.0% (children, adolescents, and young adults 1-31 years) [32] Trials of target therapies are needed MPAL 72 ± 8% (entire cohort 1-30 years), 75 ± 13% (patients on ALL regimen), 62 ± 14% (patients on AML regimen) [33] 77 ± 7% (entire cohort 1-30 years), 84 ± 9% (patients on ALL regimen), 69 ± 14% (patients on AML regimen) [33] CD19 bispecific T-cell engagers and CAR T cells [34,35], immunotherapy with blinatumomab bridge to HSCT [36,37] Abbreviations: EFS, event-free survival; OS, overall survival; Ph+ ALL, Philadelphia chromosome-positive ALL; TKI: tyrosine kinase inhibitor; Ph-like ALL, Philadelphia chromosome-like ALL; CAR, chimeric antigen receptor; HDAC, histone deacetylase; BCL2, B-cell lymphoma 2; PARP, poly(ADP-ribose) polymerase; CI, confidence interval; PI3K, phosphoinositide 3-kinase; iAMP21, intrachromosomal amplification of chromosome 21; ETP-ALL, early T-cell precursor ALL; MPAL, mixed-phenotype acute leukemia; HSCT, hematopoietic stem cell transplantation.…”