Acute Lymphoblastic Leukaemia (ALL) most often metastasise to organs such as the spleen and lymph nodes, but also to the Central Nervous System (CNS). Without CNS-directed prophylactic treatment, CNS involvement during disease progression occurs in 30-70% of patients with ALL. Furthermore, relapse in the CNS predicts poor outcome with limited treatment options due to the “blood-brain barrier” and there are currently no molecularly targeted interventions to prevent or treat CNS disease of ALL.
How cancer cells enter the CNS has been an unanswered question for researchers and clinicians for decades. Metastasis to the CNS is observed in all subtypes of ALL suggesting that lymphoblasts utilise a yet unknown, conserved, molecular mechanism to invade the CNS. Interestingly, in contrast to brain metastases from solid tumours, metastases of ALL seldom involve the parenchyma but are isolated to the leptomeninges, which is an infrequent site for carcinomatous invasion.
The enzyme PI3K has an important role transducing extracellular signals that regulate cell growth and survival. The delta isoform of PI3K (PI3Kδ) is uniquely expressed in immune cells and neurons and PI3Kδ inhibition has demonstrated significant efficacy in the treatment of lymphoid malignancies.
A recent study by Yao et al used an animal model of ALL to examine the role of PI3Kδ inhibition in ALL. Furthermore, they used this model to investigate if ALL cells in circulation were able to breach the blood-brain barrier in mice. They intravenously engrafted mice with Nalm-6 pre-B ALL cells that were derived from a patient with CNS relapse. This cell line generated a reproducible pattern of disease in mice that mimics ALL development in patients, including CNS invasion.
Yao et al found that:
PI3Kδ inhibition substantially reduced CNS disease symptoms in treated vs control mice without the PI3Kδ-inhibitor being able to penetrate the blood brain barrier.
Micro array data from ALL cells isolated from the bone marrow and the cerebrospinal fluid (CSF) identified α6 integrin as a candidate molecule involved in CNS invasion.
The laminin receptor α6 integrin is expressed in most cases of ALL and PI3Kδ inhibition decreased the α6 integrin surface expression in ALL cells.
Imaging studies tracking fluorescently labelled ALL cells could confirm that ALL cells in circulation failed to breach the blood-brain barrier in mice.
α6 integrin expression allowed cells to migrate into the CNS along vessels that pass directly between the vertebral and the subarachnoid space.
Treatment with α6 integrin neutralising antibodies reduced CNS disease symptoms in mice engrafted with Nalm-6 ALL cells and immunohistochemistry and FACS could confirm a reduction in α6 integrin expression levels and the number of ALL cells present in the leptomeningeal tissue.
Leukaemic cells have previously been shown to hijack haematopoietic stem cell trafficking mechanisms to metastasise within the bone marrow micro environment. Here, Yao et al show that ALL cells infiltrate the CNS not by breaching the blood-brain barrier, but by hijacking the neural migratory pathways. ALL cells exploited a neural stem/precursor cell embryonic pathfinding mechanism in order to bypass the vascular channels that connect the bone marrow and meninges, the predominant site of CNS ALL disease in humans. Moreover, they showed that this process can be intercepted in mouse xenograft models, providing a rationale for using clinically available PI3Kδ inhibitors to prevent CNS disease involvement in patients with ALL.