A novel BCR-ABL1 mutation in a patient with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia.

Patrícia Ribeiro,Alexandra R. Fernandes,Susana Santos,Alexandra Lourenço,Aida Botelho de Sousa,Marcos Lemos,Raquel Vinhas,Pedro V. Baptista

doi:10.2147/ott.s177019

Abstract

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) represents the most common genetic subtype of adult ALL (20%–30%) and accounts for approximately 50% of all cases in the elderly. It has been considered the subgroup of ALL with the worst outcome. The introduction of tyrosine kinase inhibitors (TKIs) allows complete hematologic remission virtually in all patients, with improved disease-free survival and overall survival. Nevertheless, the emergence of resistant mutations in BCR-ABL1 may require different TKI strategies to overcome the patient’s resistance and disease relapse. Here, we report a Ph+B-ALL case with persistent minimal residual disease (MRD) after treatment with dasatinib. The patient expressed the P190BCR-ABL1 isoform and a novel BCR-ABL1 mutation, p.Y440C. The latter is in the C-terminal lobe of the kinase domain, which likely induces deviations in the protein structure and activity and destabilizes its inactive conformation. The treatment was substituted by bosutinib, which binds to the active conformation of the protein, prior to allogeneic bone marrow transplant to overcome the lack of a complete response to dasatinib. These findings strengthen the importance of BCR-ABL1 mutational screening in Ph+ patients, particularly for those who do not achieve complete molecular remission.

Highlights

Acute lymphoblastic leukemia (ALL) is a clonal disease in which immature lymphoid cells accumulate mainly in the bone marrow and peripheral blood
The Philadelphia chromosome (Ph) is the most frequent genetic abnormality in adult ALL (Ph+ ALL), representing 20%–30% of the B-lineage cases (B-ALL) but only 5% of the pediatric cases
Mutational analysis via Sanger sequencing (“Methods” section in Supplementary materials) showed a point mutation in the ABL1 domain of the fusion transcript, c.1319A.G, which lies in the region that translates for the C-terminal lobe of the kinase domain, p.Tyr440Cys (Figure 3)

Summary

Introduction

Acute lymphoblastic leukemia (ALL) is a clonal disease in which immature lymphoid cells accumulate mainly in the bone marrow and peripheral blood. Molecular analysis of the patient’s white blood cells revealed the expression of P190BCR-ABL1 (“Methods” section in Supplementary materials and Figure S1), the most common isoform in Ph+ ALL. Mutational analysis via Sanger sequencing (“Methods” section in Supplementary materials) showed a point mutation in the ABL1 domain of the fusion transcript, c.1319A.G, which lies in the region that translates for the C-terminal lobe of the kinase domain, p.Tyr440Cys (Figure 3). Despite this variation being present in 20% of the BCR-ABL1-expressing cells at follow-up (day 29; Figure 3A2), it had not been identified at diagnosis (day 1; Figure 3A1). He died 7 months posttransplant from complications of acute graft vs host disease

Discussion

Findings

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