3. Mechanisms

The precise mechanism underlying the development of MS is unclear. However, extramedullary infiltration by acute leukemia strongly implicates the presence of an alternative homing signal that enables the blast cells to re-localize to these secondary sites. In this context, strong evidence was provided by the studies demonstrating the presence of different chemokine receptors on blast cells in MS and concurrent AML involving blood and bone marrow [16]. Taken together, these observations led to the proposal that unusual manifestations of adhesion molecules dictate the migration of AML subclones to surrounding tissues. Stefanidakis et al. provided further insights into the migratory capacity of blast cells. In their study, the authors reported that a major factor for the migration of AML cells into non-myeloid regions is the interactions between matrix metalloproteinase (MMP) – 9 and leukocyte β2 integrin along with some unidentified proteins [2]. Stefanidakis et al. termed the complex, 'invadosome' [2]. The observations that highly invasive AML cell lines express high level of MMP-2 and tissue inhibitor of metalloproteinase 2 (TIMP2) further support the conclusion of Stefanidakis and colleagues [17]. In a recent study, Zhu et al. has reported a correlation between high expression of enhancer of Zeste 2 (EZH2), the catalytic subunit of polycomb repressor complex 2 (PRC2), and extramedullary infiltration of AML [18]. The authors have indicated that increased expression of EZH2 attenuates the expression of TIMPs, which result in the upregulation of MMPs. The uninhibited MMPs ultimately degrades the extracellular matrix (ECM) and thus aid in the escape of the blast cells in the extramedullary space [18].
