Tackling Acute Lymphoblastic Leukemia—One Fish at a Time

Abstract

Despite advancements in the diagnosis and treatment of acute lymphoblastic leukemia (ALL), a need for improved strategies to decrease morbidity and improve cure rates in relapsed/refractory ALL still exists. Such approaches include the identification and implementation of novel targeted combination regimens, and more precise upfront patient risk stratification to guide therapy. New curative strategies rely on an understanding of the pathobiology that derives from systematically dissecting each cancer’s genetic and molecular landscape. Zebrafish models provide a powerful system to simulate human diseases, including leukemias and ALL specifically. They are also an invaluable tool for genetic manipulation, in vivo studies, and drug discovery. Here, we highlight and summarize contributions made by several zebrafish T-ALL models and newer zebrafish B-ALL models in translating the underlying genetic and molecular mechanisms operative in ALL, and also highlight their potential utility for drug discovery. These models have laid the groundwork for increasing our understanding of the molecular basis of ALL to further translational and clinical research endeavors that seek to improve outcomes in this important cancer.

The lncRNA SLCO4A1‐AS1/miR‐876‐3p/RBBP6 axis regulates cell proliferation and apoptosis in acute lymphocytic leukemia via the JNK signaling pathway

“…Though in high‐income countries, five‐year survival rate for ALL children and adolescents has increased to more than 90%, the prognosis of some patients (older than 40 years old) is still poor on account of relapse and the side effects of chemotherapy 2‐4 . In recent years, molecular therapeutic therapy to tackle ALL is getting more and more attention 5 . Therefore, understanding molecular mechanisms under ALL pathogenesis is advantageous to develop new strategies for treatment of ALL.…”

Genetic Engineering of Zebrafish in Cancer Research

“…In their princeps experiments, Langenau and colleagues [ 121 ] used the rag2 promoter to drive expression of the Myc oncogene and induce T-ALL. However, since B-lymphoblasts also express rag2 and because MYC is known to drive human B-ALL, the Tg(rag2:GFP-Myc) and Tg(rag2:MYC) transgenic zebrafish also develop B-ALL [ 123 , 124 , 125 , 126 ]. While the rag2 gene shows a specific expression in immature lymphoid cells, the zebrafish rag2 promoter used in transgenics is active in both lymphoid and nonlymphoid cell populations including olfactory rosettes, sperm and mesenchymal progenitor cells [ 127 , 128 , 129 ].…”

Development of BCR-ABL1 Transgenic Zebrafish Model Reproducing Chronic Myeloid Leukemia (CML) Like-Disease and Providing a New Insight into CML Mechanisms

“…Transgenic technology enables the generation of specific types of tumors by the expression of human oncogenes under tissue specific promoters. The vast majority of zebrafish leukemia models relies on overexpression of proto-oncogenes that are deregulated in different human hematologic malignancies, such as acute myeloid leukemia [ 6 , 7 ], acute lymphoblastic leukemia [ 8 , 9 ]; chronic lymphocytic leukemia [ 10 ]; and lymphomas [ 9 , 11 ]. The described pathologies are characterized by relevant multiple genetic mutations, but in many cases they are not good models because rarely the pathogenic mechanism and progression of neoplastic disease is due to a single driver mutation [ 12 , 13 ].…”