B-Lymphoblastic Leukemia/Lymphoma with TCF3 Rearrangements - Excluding t(1;19) and t(12;19)
Celeste Eno, PhD, Cedars-Sinai Medical Center
B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) with TCF3 variant fusions
Cancer Sub-Classification / Subtype
TCF3::HLF Fusion t(17;19)(q22;p13.3)
Definition / Description of Disease
B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) with TCF3::HLF harbors a translocation between TCF3 on chromosome 19 and HLF on chromosome 17. Variant TCF3 fusions are not associated with the WHO-classified entity, t(1;19), due to a difference in prognosis although the clinical features and immunoprofiles are reportedly similar.
Synonyms / Terminology
Epidemiology / Prevalence
The presenting features are generally similar to those seen in patients with other ALL categories. Specific symptoms which have been noted to be associated with t(17;19) include coagulopathy and hypercalcemia. Patients with TCF3::HLF Type I fusions have been suggested to be associated with disseminated intravascular coagulation. Patients with TCF3::HLF Type II fusions have been associated with hypercalcemia. It has been hypothesized that hypercalcemia in t(17;19) patients is partly parathyroid hormone-related protein (PTHrP) mediated.
|Signs and Symptoms||B-symptoms (weight loss, fever, night sweats)
Type II: Hypercalcemia
Sites of Involvement
Bone Marrow and Peripheral Blood
There are no unique morphological or cytochemical features that distinguish this entity from other types of ALL.
t(17;19) display an immunoprofile similar to t(1;19). Cases of t(1;19)-ALL with concomitant TCF3::PBX1 fusion invariably express a characteristic but uncommon profile of surface antigens. Blasts typically have a pre-B phenotype, with positivity for CD19, CD10, and cytoplasmic mu heavy chain. This diagnosis can be suspected even when cytoplasmic mu is not determined because these leukemias typically show strong expression of CD9 and lack CD34 or show very limited CD34 expression on only a minor subset of leukemic cells.
|Positive (universal)||Cytoplasmic µ (cµ) heavy chain (pre-B phenotype); strong CD9; CD10; CD19|
|Negative (universal)||CD34; CD20 (Partial); CD21; Surface Immunoglobulin|
Chromosomal Rearrangements (Gene Fusions)
TCF3 encodes several transcription factors via alternative splicing. t (17;19) occurs in rare cases of ALL involving HLF (hepatic leukemia factor) on chromosome 17. The TCF3::HLF fusion gene encodes a chimeric transcription factor in which the transactivation domain of TCF3 links to the basic leucine zipper dimerization and DNA-binding domain of HLF. There are two types of fusion: type 1 is generated by the fusion between exon 16 of TCF3 and exon 4 of HLF with an insertion of cryptic exon (joining region) maintaining an open-reading frame, whereas type 2 is generated by the fusion between exon 15 of TCF3 and exon 4 of HLF in the same reading frame.
|Chromosomal Rearrangement||Genes in Fusion
(5’ or 3’ Segments)
|Pathogenic Derivative||Prevalence||Diagnostic Significance (Yes, No or Unknown)||Prognostic Significance (Yes, No or Unknown)||Therapeutic Significance (Yes, No or Unknown)||Notes|
|t(17;19)(q22;p13)||5' TCF3 / 3' HLF||der(19)||<1%||Yes||Yes||No||There are two types of fusion: type 1 is generated by the fusion between exon 16 of TCF3 and exon 4 of HLF with an insertion of cryptic exon (joining region) maintaining an open-reading frame, whereas type 2 is generated by the fusion between exon 15 of TCF3 and exon 4 of HLF in the same reading frame.|
Characteristic Chromosomal Aberrations / Patterns
Only a few cases have been reported; therefore, no characteristic patterns are noted as of yet. However, ~50% of cases may contain additional abnormalities
Only a few cases have been reported; therefore, no characteristic patterns are noted as of yet. One case demonstrated loss of 13q12.2q21.1 (containing RB1) and intergenic duplication of NOTCH1. It has described that up to 70% of TCF3::HLF cases have a concurrent PAX5 deletion
Gene Mutations (SNV/INDEL)
Very few studies have reported findings, and such studies focus on the specific fusion type. A study comparing t(1;19) (n=29) to t(17;19) (n= 12) cases reported recurrent intragenic deletions of PAX5 or VPREB1 in 2 cases of t(17;19) and RAS signaling pathway genes in 2 cases. Additionally a study of four t(17;19)‐ALL cell lines detected RAS pathway mutations in all four t(17;19)‐ALL lines.
|Gene; Genetic Alteration||Presumed Mechanism (Tumor Suppressor Gene (TSG)/Oncogene/Other)||Prevalence (COSMIC/ TCGA/Other)||Concomitant Mutations||Mutually Exclusive Mutations||Diagnostic Significance (Yes, No or Unknown)||Prognostic Significance
(Yes, No or Unknown)
(Yes, No or Unknown)
|RAS family (NRAS, KRAS, PTPN11, SPHK1); Activating mutations|
|TCF3||One study found TCF3 mutations on the non-fused, normal allele in relapsed/progressing cases.|
A single study comparing t(17;19) with t(1;19) found 7000 differentially methylated CpG sites between subtypes, of which 78% had lower methylation levels in TCF3::HLF. KBTBD11 differed in methylation and expression between subtypes and before and after remission in TCF3::HLF samples.
Genes and Main Pathways Involved
The chimeric protein from TCF3::HLF acts as a transcription factor resulting in dedifferentiation of mature B lymphocytes. All TCF3 fusions had expression profile signature of B lymphoid cells (PAX5, BLK, CD19, CD22, CD79B, TCF3, EBF1, VPREB1, RAG1, ROR1, BLNK, DNTT). The differences between the TCF3 fusion partners, PBX1, HLF, and ZNF384, led to differential expression patterns based on the genes regulated by these partners. t(17;19) demonstrated induced expression of HLF- regulated genes (SNAI2 (SLUG), GPC4 and BMP3).
|Gene; Genetic Alteration||Pathway||Pathophysiologic Outcome|
|TCF3::HLF||Dedifferentiation of mature B lymphocytes|
Diagnostic Testing Methods
- Chromosome analysis
- Fluorescence in situ hybridization (FISH). Break-apart probes may be required to identify cases with cryptic translocations.
- Reverse transcriptase PCR (RT-PCR) may aid in diagnosis.
- Next generation sequencing (NGS)
- Mate pair sequencing (MPseq) to identify the fusion partners in G-band negative, TCF3 BA + cases.
Determination of the fusion partner is necessary as there are significant prognostic differences between the recurrent TCF3::PBX1 fusion and the less common fusions of TCF3::HLF or TCF3::ZNF384.
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
The TCF3::HLF translocation, t (17;19), is associated with a dismal prognosis. A study found t(17;19) may be sensitive to certain drugs in animal models. An in vitro study using four t(17;19)‐ALL and sixteen t(1;19)‐ALL cell lines demonstrated the t(17;19)‐ALL cell lines were more resistant to vincristine (VCR), daunorubicin (DNR), and prednisolone (Pred) than t(1;19)‐ALL cell lines. In addition the t(17;19)‐ALL cell lines were less sensitive to three (Pred, VCR, and l‐asparaginase [l‐Asp]), four (Pred, VCR, l‐Asp, and DNR) and five (Pred, VCR, l‐Asp, DNR, and cyclophosphamide) agents, which are widely used in induction therapy.
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