Importance of Rare Gene Alterations in the Prognosis of B-Cell Acute Lymphoblastic Leukemia

To the Editor,

We read the recently published study by Ray et al. [1] with great interest. They reported amplification of the BCR::ABL1 fusion gene as a rare phenomenon in B-cell acute lymphoblastic leukemia (ALL). In their study, BCR::ABL1 and ETV6::RUNX1 translocations, TCF3 and KMT2A rearrangements, and the t(9,22)(q34;q11) BCR::ABL1 translocation were revealed by fluorescent in situ hybridization (FISH) along with multiple copies of the fusion gene appearing separately in a patient with B-cell ALL as a rare case. This patient died within a month of the diagnosis.

However, the two major isoforms of the oncogenic BCR-ABL1 tyrosine kinase, p210 and p190, were not mentioned in the context of this patient’s case. p210 is the hallmark of chronic myelogenous leukemia, whereas p190 occurs in the majority of B-cell ALL cases [2]. The resulting fusion oncogene is a tyrosine kinase, which in turn results in the uncontrolled proliferation of cells. Importantly, the combination of chemotherapy with second- or third-generation tyrosine kinase inhibitors further improved the outcomes of BCR-ABL1-positive B-cell ALL patients [3]. However, in the case discussed here, the BCR-ABL1 tyrosine kinase p210 and p190 status of the patient and the possible use of tyrosine kinase inhibitors such as imatinib or dasatinib remains unclear since the patient died within a month of diagnosis.

Besides the BCR::ABL1 translocation, the ETV6::RUNX1 translocation and TCF3 and KMT2A rearrangements were also revealed in this patient. Among these genes, ETV6-RUNX1 is the most frequent genetic fusion in pediatric B-ALL. The distinct KMT2A rearrangements are independent dismal prognostic factors, and TCF3 gene rearrangements were also described as being associated with significant differences in ALL prognosis [4,5]. As we know, the molecular hallmark of ALL entails recurrent prognostic genetic alterations, many of which are cryptic by conventional cytogenetics [5,6]. Thus, Ray et al. [1] highlighted the need for FISH or other conventional cytogenetic approaches over reverse-transcriptase polymerase chain reaction studies to confirm disease progression. However, FISH only uses several commercial probes, resulting in limited results for rare genes. Therefore, besides FISH, we want to emphasize that whole-genome sequencing could provide standalone, reliable genetic testing to detect all subtype-defining genetic abnormalities in B-ALL, accurately classifying patients for risk-directed treatment stratification [7]. Moreover, RNA sequencing is also a powerful next-generation sequencing technology that can simultaneously identify cryptic gene rearrangements, sequence mutations, and gene expression profiles in a single assay, including genetic alterations not detected by conventional methods that confer potential prognostic and therapeutic impact [6]. Thus, in addition to FISH, we suggest that whole-genome sequencing or RNA sequencing could be better tools to more accurately classify ALL patients for risk-directed treatment stratification.