TCF3::HLF acute lymphoblastic leukemia: still challenging to cure thirty years later

TITLE Two types of genomic rearrangements create alternative E2A-HLF fusion proteins in t(17;19)-ALL.

AUTHORS Hunger SP, Devaraj PE, Foroni L, Secker-Walker LM, Cleary ML.

JOURNAL Blood. 1994;83(10):2970-2977. PMID: 8065331.

While the majority of children, adolescents, and young adults with B-cell acute lymphoblastic leukemia (B-ALL) can be cured by risk-adapted multi-agent chemotherapy regimens optimized during the past 50 years, long-term survival has remained elusive for pediatric patients with the rare (<1% of cases), but to date universally-fatal, t(17;19) subtype harboring TCF3::HLF (formerly E2A-HLF) fusions first identified and reported in 1991.¹ A landmark study by Dr Stephen Hunger and colleagues in 1994² cloned and further defined the two major TCF3::HLF fusion breakpoints that are now known to be associated with highly characteristic clinical presentations in patients with this deadly form of B-ALL (Figure 1). Type 1 rearrangements result in translocation between exon 13 of TCF3 and exon 4 of HLF and are associated with a severe disseminated intravascular coagulation phenotype. Type 2 rearrangements result in translocation between exon 12 of TCF3 and exon 4 of HLF and induce a severe hypercalcemia phenotype. The precise mechanisms of these phenomena remain incompletely elucidated. Such clinical manifestations are extremely unusual in other B-ALL subtypes and provide important early clues regarding potentially worrisome leukemia-associated genetic alterations to be detected via cytomolecular assays. Regardless of the specific t(17;19) breakpoints and distinctive clinical phenotypes, patients with TCF3::HLF B-ALL have poor initial responses to chemotherapy and/or experience early relapses (usually within two years of diagnosis) that have been unsalvageable to date with intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT) in first remission.

Figure 1.Two genomic rearrangements within t(17;19)(q22;p13) acute lymphoblastic leukemia induce unique clinical phenotypes. Type I rearrangements (upper panel) involving E2A (now TCF3) exon 13 and HLF exon 4 are associated with disseminated in-travascular coagulation. Type II rearrangements (lower panel) involving E2A exon 12 and HLF exon 4 are associated with hypercalcemia. The uncommon TCF3::HLF B-ALL subtype occurs almost exclusively in pediatric patients, most commonly in adolescence. (Figure adapted with permission from Hunger et al. Blood 1994).²

Chemoresistance in TCF3::HLF B-ALL has been attributed in part to upregulation of P-glycoprotein expression and ABC multi-drug resistance transport proteins and to upregulation of RAS, BCL-2, and other pro-survival pathways. Recent preclinical studies based upon gene expression characterization and biochemical high-throughput drug screening of primary TCF3::HLF ALL specimens have identified potential Achilles’s heels for targeted therapies, including MEK inhibition (also germane given frequent KRAS or NRAS co-mutations), BH3 family protein inhibition with navitoclax and/or venetoclax, SRC family kinase inhibition with dasatinib, and Aurora kinase inhibition with alisertib.³ However, such precision medicine approaches have not been widely evaluated in the clinic given the relative rarity of patients with TCF3::HLF B-ALL.

As in other relapsed/refractory B-ALL subtypes, there is tremendous interest in learning if paradigm-shifting CD19-targeted or CD22-targeted antibody-based or cellular immunotherapies will ultimately be able to declare victory over the TCF3::HLF B-ALL villain. Encouragingly, recent case series have reported successful remission induction in a small number of patients with relapsed/refractory TCF3::HLF B-ALL treated with blinatumomab-to-HSCT or CD19 chimeric antigen receptor T cells,^4,5 although most children have experienced subsequent relapse with longer follow-up. Further studies are necessary to determine if these promising immunotherapeutic approaches are truly high-risk genetics-agnostic and can be further optimized for long-term cure of the unique, and quite deadly, TCF3::HLF B-ALL subtype.

Footnotes

Correspondence

tasians@chop.edu

Disclosure

No conflicts of interest to disclose.