Myosin-IIA regulates leukemia engraftment and brain infiltration in a mouse model of acute lymphoblastic leukemia

Abstract

Leukemia dissemination (the spread of leukemia cells from the bone marrow) and relapse are associated with poor prognosis. Often, relapse occurs in peripheral organs, such as the CNS, which acts as a sanctuary site for leukemia cells to escape anti-cancer treatments. Similar to normal leukocyte migration, leukemia dissemination entails migration of cells from the blood circulation into tissues by extravasation. To extravasate, leukemia cells cross through vascular endothelial walls via a process called transendothelial migration, which requires cytoskeletal remodeling. However, the specific molecular players in leukemia extravasation are not fully known. We examined the role of myosin-IIA a cytoskeletal class II myosin motor protein, in leukemia progression and dissemination into the CNS by use of a mouse model of Bcr-Abl-driven B cell acute lymphoblastic leukemia. Small hairpin RNA-mediated depletion of myosin-IIA did not affect apoptosis or the growth rate of B cell acute lymphoblastic leukemia cells. However, in an in vivo leukemia transfer model, myosin-IIA depletion slowed leukemia progression and prolonged survival, in part, by reducing the ability of B cell acute lymphoblastic leukemia cells to engraft efficiently. Finally, myosin-IIA inhibition, either by small hairpin RNA depletion or chemical inhibition by blebbistatin, drastically reduced CNS infiltration of leukemia cells. The effects on leukemia cell entry into tissues were mostly a result of the requirement for myosin-IIA to enable leukemia cells to complete the transendothelial migration process during extravasation. Overall, our data implicate myosin-IIA as a key mediator of leukemia cell migration, making it a promising target to inhibit leukemia dissemination in vivo and potentially reduce leukemia relapses.

Leukemia-derived exosomes and cytokines pave the way for entry into the brain

“…Future work is expected to shed light on the mechanistic roles for IL‐15‐mediated signaling in brain metastasis. In addition to the potential for an IL‐15/IL‐15R auto/paracrine axis, feedback loops may result in upregulation of cytokine and chemokine receptors that mediate lymphoblastic infiltration into meningeal spaces and/or intracellular players that govern transmigration, such as myosin‐IIA . The NALM6 model may be particularly useful for understanding processes that lead to leukemia invasion of brain parenchyma, which was associated with only 10% of cases in a 1972 study of 126 autopsies .…”

“…In addition to the potential for an IL-15/IL-15R auto/paracrine axis, feedback loops may result in upregulation of cytokine and chemokine receptors that mediate lymphoblastic infiltration into meningeal spaces [25][26][27] and/or intracellular players that govern transmigration, such as myosin-IIA. 62 The NALM6 model may be particularly useful for understanding processes that lead to leukemia invasion of brain parenchyma, which was associated with only 10% of cases in a 1972 study of 126 autopsies. 35 Case reports of intracerebral metastases remain relatively rare 32,37,38 ; because these cases were all associated with relapse, it is possible that occasional intraparenchymal colonies can offer leukemia cells sanctuary from standard treatments.…”

The Formin mDia1 Regulates Acute Lymphoblastic Leukemia Engraftment, Migration, and Progression in vivo

“…Phase contrast and fluorescent images were acquired every 15–25 s using a 20X Phase-2 objective for 30 min long time-lapses using a Spinning Disk confocal microscope with environmental control (Intelligent Imaging Innovations) and Slidebook imaging software (Intelligent Imaging Innovations). Using similar criteria as previously described ( 11 , 29 ), a cell was scored as having undergone transendothelial when it lost its white phase ring in a step-wise process during the course of the time-lapse.…”

“…Furthermore, data have shown that genes involved in cytoskeletal remodeling and cell migration play an important role in lymphoma progression in vivo ( 10 ). We recently reported that the cytoskeletal motor protein Myosin-IIA is required for leukemia migration, progression and entry into the Central Nervous System ( 11 ). However, the role of specific cytoskeletal effector proteins in leukemia migration and progression in vivo is largely unknown.…”

Myosins as fundamental components during tumorigenesis: diverse and indispensable

“…Proteomic analysis has suggested that in breast cancer cells, MHC (myosin heavy chain) phosphorylation sites were activated during integrin engagement and lamellar extension on fibronectin [30]. Although myosin II is not indispensable for the nascent formation of lamellipodium, it is truly essential to the subsequent cell's elongation and growth [124–125]. The assembly dynamics of myosin II's interaction with integrin engagement plays important roles in regulating the components of cancer cell migration during tissue setting [45].…”