Meg Meagher

Acute lymphoblastic leukemia (ALL) is a blood cancer of T or B lymphocytes that originates in the bone marrow, but frequently involves other organs including the central nervous system (CNS). In the context of the CNS, the standard ALL treatment of chemotherapy is toxic and ineffective at targeting all leukemia cells. As a result, ALL relapses in the CNS are common and many patients suffer from both acute and long-term neurocognitive side effects. One mechanism by which leukemia cells evade chemotherapy, survive and proliferate is through manipulation of the microenvironment, or niche. In the CNS niche, chemotherapy evasion and leukemia cell survival is achieved through interactions with and cellular adhesion to the meninges, or the thin layer of cells that covers the brain and spinal cord. However, how these interactions change meningeal cell biology and contribute to chemoresistance is unknown, as is whether these effects can be reversed by targeting the meningeal niche cells. Here we show that the AKT pathway is upregulated in primary meningeal cells isolated from an in-vitro co-culture with Jurkat leukemia cells. Moreover, administration of an AKT inhibitor reverses this change and, importantly, reduces leukemia cell chemoresistance and viability in meningeal co-culture experiments. While niche cell manipulation by leukemia cells has been demonstrated in other microenvironments, the AKT upregulation in meningeal cells translates this finding to the CNS. Within the CNS, our results demonstrate the effectiveness of an AKT pathway inhibitor at decreasing leukemia viability and chemoresistance. We anticipate that the results of this work will support the combination of AKT pathway inhibitors with chemotherapy to treat CNS leukemia. Within the CNS, this would allow for a decrease in the incidence of relapse for ALL patients as well as less therapy-related toxicities.