Dasatinib and chemotherapy in a patient with early T‑cell precursor acute lymphoblastic leukemia and NUP214‑ABL1 fusion: A case report

Abstract

The present study aimed to evaluate the therapeutic efficacy of dasatinib in a patient with nucleoporin 214-tyrosine protein kinase ABL1 proto-oncogene 1 (NUP214-ABL1)-positive early T-cell precursor-acute lymphoblastic leukemia (ETP-ALL), as well as that of selinexor and dasatinib for NUP214-ABL1-positive ETP-ALL in vitro. ETP leukemia is a form of T-cell ALL (T-ALL) with poor prognosis. The NUP214-ABL1 gene is present in ~6% of T-ALL cases, however the prevalence of NUP214-ABL1 gene expression in ETP-ALL in particular has not yet been verified. The current study reports the rare case of a 29-year-old man with ETP-ALL harboring the NUP214-ABL1 fusion gene, presenting with low-grade fever, stomachache and splenomegaly. The patient was successfully treated with dasatinib and vincristine, idarubicin, cyclophosphamide and prednisone (VICP) chemotherapy. The therapeutic efficacy of selinexor and dasatinib was also evaluated in vitro. Apoptosis was analyzed using Annexin V/propidium iodide staining and flow cytometry, and poly ADP-ribose polymerase (PARP) cleavage was detected using western blot analysis. The results demonstrated that the apoptotic cell population significantly increased following selinexor or dasatinib treatment compared with the control (P<0.05). Furthermore, combined selinexor and dasatinib treatment led to a significant increase in cell apoptosis compared with either treatment alone (P<0.05). The apoptosis results were confirmed by PARP cleavage. Thus, NUP214-ABL1 fusion gene expression should be tested in T-ALL, including ETP-ALL. Dasatinib used in combination with traditional induction chemotherapy may reverse the high induction failure of ETP-ALL with NUP214-ABL1 fusion gene; however, further prospective studies are required to confirm this. Therefore, selinexor with or without dasatinib may serve as a potential salvage therapy in the case of relapse and may be developed as a novel treatment for ETP-ALL with the NUP214-ABL1 fusion gene.

Whole‐exome sequencing reveals the subclonal expression of NUP214‐ABL1 fusion gene in T‐cell acute lymphoblastic leukemia

“…Besides the present case, two case reports have described instability of NUP214‐ABL1 fusion. One case lost NUP214‐ABL1 fusion at relapse similar to our case. In the other case, EML1‐ABL1 fusion at diagnosis was taken place by NUP214‐ABL1 at relapse .…”

“…2 NUP214-ABL1 fusion leads to constitutive ABL1 kinase activity, serving as a potential target of TKIs in the treatment of NUP214-ABL1-positive T-ALL. [3][4][5][6][7] Monitoring expression of the fusion gene is of clinical significance in some cases with leukemia. In the case of NUP214-ABL1 fusion, which may exist on amplified episomes, copy numbers of the fusion gene can diverge subclonally that could result in discordance between the fusion gene expression levels in samples and the actual amount of residual disease.…”

“…The NUP214‑ABL1 fusion gene is identified in ∼6% of pediatric and adult patients with T‐cell acute lymphoblastic leukemia (T‐ALL) . NUP214‐ABL1 fusion leads to constitutive ABL1 kinase activity, serving as a potential target of TKIs in the treatment of NUP214‐ABL1 ‐positive T‐ALL . Monitoring expression of the fusion gene is of clinical significance in some cases with leukemia.…”

Can one target T-cell ALL?

“…NUP214-ABL1 is frequently associated with the TLX1 and TLX3 group of T-ALLs and although it can be found as a subclonal alteration and does not appear to be linked with poor prognosis, it can be effectively blocked with tyrosine kinase inhibitors [43]. To date only a handful of NUP214-ABL1 positive patients have been treated with a tyrosine kinase inhibitor, yet these drugs seem to be active, demonstrating preclinical biomarkers of activity and could provide clinical benefit in some cases [44–46] (Figure 1). …”

Detection of a cryptic NUP214/ABL1 gene fusion by mate-pair sequencing (MPseq) in a newly diagnosed case of pediatric T-lymphoblastic leukemia

“…Although recurrent genetic abnormalities in many hematologic neoplasms add diagnostic, prognostic, and therapy-related value, the clinical significance of the known recurrent genetic abnormalities observed in T-ALL are mostly unclear or controversial (Borowitz et al 2017; Taylor et al 2017). Interestingly, the detection of ABL1 gene rearrangements, which are often associated with BCR/ABL1 -positive B-ALL and BCR-ABL1 -like (Ph-like) B-ALL (Pui et al 2017; Tasian et al 2017), have also been described in T-ALL—namely, NUP214 / ABL1 —and may be amenable to tyrosine kinase inhibitor (TKI) therapy (Graux et al 2004; Burmeister et al 2006; Quintás-Cardama et al 2008; Deenik et al 2009; Graux et al 2009; Hagemeijer and Graux 2010; Clarke et al 2011; De Braekeleer et al 2011; Duployez et al 2016; Simioni et al 2016; Chen et al 2017; Liu et al 2017). Considering the limited treatment options and overall unfavorable prognosis of T-ALL, detecting genetic abnormalities that may respond to targeted therapy is critical.…”