Identification and characterization of a murine model of BCR‑ABL1+ acute B‑lymphoblastic leukemia with central nervous system metastasis

Abstract

Breakpoint cluster region (BCR)-Abelson murine leukemia (ABL)1 + acute B-lymphoblastic leukemia (B-ALL) is a disease associated with a dismal prognosis and a high incidence of central nervous system (CNS) metastasis. However, BCR-ABL1 + B-ALL with CNS infiltration has not been previously characterized, at least to the best of our knowledge. In the present study, a murine model of BCR-ABL1 + B-ALL with CNS metastasis was established using retroviral transduction. The vast majority of BCR-ABL1 + leukemic cells were found to be immature B cells with a variable proportion of pro-B and pre-B populations. The present results indicated that the BCR-ABL1 + B-leukemic cells expressed high levels integrin subunit alpha 6 (Itga6) and L-selectin adhesion molecules, and have an intrinsic ability to disseminate and accumulate in CNS tissues, predominantly in meninges. On the whole, these results provide an approach for addressing the mechanisms of BCR-ABL1 + B-ALL with CNS metastasis and may guide the development of novel therapeutic strategies.

Involvement of the central nervous system in acute lymphoblastic leukemia: opinions on molecular mechanisms and clinical implications based on recent data

“…However, it appears that CNS disease in BCR-ABL1-positive ALL shares some common features and pathways with other cytogenetic subtypes with CNS tropism. Different in vivo model systems of BCR-ABL-positive ALL based on the introduction of a BCR-ABL1 fusion gene into murine bone marrow cells showed profound infiltration of the CNS [39,57]. One study in a mouse model of BCR-ABL positive leukemia with CNS tropism found the upregulation of L-selectin and integrin subunit alpha 6 (Itga6) in BCR-ABL expressing cells compared to control cells [57].…”

“…Different in vivo model systems of BCR-ABL-positive ALL based on the introduction of a BCR-ABL1 fusion gene into murine bone marrow cells showed profound infiltration of the CNS [39,57]. One study in a mouse model of BCR-ABL positive leukemia with CNS tropism found the upregulation of L-selectin and integrin subunit alpha 6 (Itga6) in BCR-ABL expressing cells compared to control cells [57]. By this, BCR-ABL-positive cells may be prone to adhere to CNS vessels and to utilize the vascular entry routes described above.…”

Co-Detection of VEGF-A and Its Regulator, microRNA-181a, May Indicate Central Nervous System Involvement in Pediatric Leukemia

“…The absence of ITGA6 in BM and CSF supernatants gained by cell removal in our study claims that this cell surface protein of blast cells may not be likely to be involved in integrin shedding or such process allocating ITGA6 into the extracellular space. Previously, high ITGA6 expressions were measured inside the CNS-invading leukemic cells [ 14 ].…”

Metabolic Reprogramming and Cell Adhesion in Acute Leukemia Adaptation to the CNS Niche

“…ALL xenografts treated with specific α6 integrinneutralizing antibodies showed reduced leukemia burden in the CSF/meninges. High levels of Itga6 mRNA (encodes α6) were also found in leukemic cells in a BCR-ABL1-driven murine model of meningeal leukemia (Yu et al, 2019). On the contrary, recent studies identified ITGA5 (α5) and ITGA9 (α9) expression positively correlated with CSF colonization in primary B-ALL samples (Scharff et al, 2020a;Scharff et al, 2020b).…”