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Available information indicates that the prognosis of EML is Expression of matrix metalloproteases may contribute to
poor with short overall survival. In an evaluation, the the increased incidence of EMI in some subtypes of AML.
[11]
5-year survival rate for patients with MS was 21%. Patients For example, in SHI-1 cells, a highly invasive human acute
treated with chemotherapy showed longer survival than monocytic leukemia cell line, there is a high expression
untreated patients. Although the mortality rate of acute level of matrix metalloproteinase 2 (MMP-2), membrane-
[35]
leukemia patients has been reduced with the emergence of type 1 MMP and tissue inhibitor of metalloproteinase,
new therapies, many patients still suffer from refractory which facilitate cell invasion. Moreover, it has been
[40]
disease or relapse, and EMI is one of the main causes of suggested that the specific binding of MMP-9 via its
poor prognosis in these patients. [8] procatalytic domain to leukocyte surface I domains of
beta-2 integrins is essential for precellular proteolysis and
EXTRAMEDULLARY NICHE IN AML migration of AML-derived cells [Table 1].
[41]

During development, HSCs are initially present in AGM and MICRORNAS’ SIGNIFICANCE IN
then migrate into the fetal liver and embryonic bone, which EXTRAMEDULLARY AML
remains the only active site of hematopoiesis in adult life.
Movement and homing of HSCs in the BM is associated MicroRNAs (miRNAs) are small, 18-25 nucleotide non-
with CXCL12 chemokine and its receptor CXCR4. Cancer coding RNA molecules, which regulate gene expression
[36]
subverts cell-cell and matrix-cell interactions and converts by hybridizing to their complementary messenger RNA.
the normal niche to a neoplastic one. [37] Each miRNA has the potential to regulate several different
transcripts through partially complementary target
ITD-FLT3 mutation, which is common in AML and MS sequences. miRNAs participate in cell differentiation,
[56]
patients, leads to deregulation of CXCR4 in AML leukemic proliferation and carcinogenesis. Several studies have
cells since CXCR4 signaling is markedly decreased in shown that miRNAs play key roles in normal hematopoiesis
patients with ITD-FLT3 compared with patients without it. and various hematological malignancies. Different miRNAs
It is thought that this mutation facilitates the infiltration of are also known in myelopoiesis and myeloid neoplasias
[57]
leukemic cells into visceral organs by reducing the homing of like AML. Functional studies have shown that miRNAs
leukemic cells. Infiltration of leukemic cells in other organs play an important role in the pathogenesis of AML as either
[38]
is likely associated with chemokine receptor expression and oncogenes or tumor suppressors. It has also been shown that
different adhesion molecules. For example, NCAM1 or distinct miRNA expression signatures are associated with
[58]
CD56, which is associated with a high incidence of MS, is response to chemotherapy and clinical outcomes. Based
highly expressed in the breast, testicular tissue, ovary and on our literature and database searches, there has been no
gut. This molecule is responsible for homing of leukemic study describing miRNA signatures in MS. However, some
cells in these tissues. Moreover, AML blasts isolated from studies show a link between miRNAs and mutation-induced
[11]
skin show a group of specific chemokine receptors including MS. MiR-100 is aberrantly expressed in a number of cancer
CCR5, CXCR4, CXCR7, and CX3CR1 compared with cells, including AML cells. Increased expression of miR-100
AML blasts isolated from blood and BM. These cytokine- in AML is associated with maturation block. In vitro studies
cytokine receptor interactions enable homing and survival of indicate that increased expression of miR-100 in AML cells
AML blasts in skin [Figure 1]. [39] inhibits retinoblastoma 1 serine phosphates from human
chromosome 3 and causes the release of E2F in addition to
increased levels of phosphorylated retinoblastoma. These
events induced proliferation and inhibited the differentiation
of granulocyte/monocyte cells. In a study performed on
[59]
106 pediatric AML patients, it showed that this miRNA was
associated with AML with extramedullary manifestation. [60]
High expression level of miR-10 family is associated
with AML with mutated NPM-1. [25,61] Furthermore,
miR-424 in AML patients with NPM-1 mutation was
down-modulated. In AML patients with the FLT3-ITD
[62]
mutation, miR-451 and miR-144 were down-regulated
Figure 1: Extramedullary infiltration formation process in acute myeloid leukemia. while miR-155 was overexpressed. As previously
[63]
(A) Within deregulation of LSCs located in BM, cell links with niche will be cut,
and then they will enter into the circulation via BM sinusoids; (B) disseminated mentioned, NPM-1 and FLT3-ITD mutations, as well as
LSCs circulate in blood vessels and based on their special characteristics, enter some other cytogenetic abnormalities, are associated with
specific tissue, like skin; (C) leukemic cells, along with new, distinct niche, initiate
new tumor in metastatic tissue. The exact molecular and cellular characteristics increased risk of EMI. [25,27,28] In summary, deregulated
have not been defined completely. SDF-1: stromal cell-derived factor 1; BM: miRNAs in these disorders can be considered as candidate
bone marrow; LSC: leukemic stem cells; HSC: hematopoietic stem cell; CAR cell:
CXCL12-abundant reticular cell markers for future studies in MS patients [Table 2].
46
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ Issue 2 ¦ February 29, 2016 ¦