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Zorn, K.E.; Cunningham, A.M.; Meyer, A.E.; Carlson, K.S.; Rao, S. Biological Understandings of Pathogenesis. Encyclopedia. Available online: https://encyclopedia.pub/entry/42134 (accessed on 13 July 2025).
Zorn KE, Cunningham AM, Meyer AE, Carlson KS, Rao S. Biological Understandings of Pathogenesis. Encyclopedia. Available at: https://encyclopedia.pub/entry/42134. Accessed July 13, 2025.
Zorn, Kristin E., Ashley M. Cunningham, Alison E. Meyer, Karen Sue Carlson, Sridhar Rao. "Biological Understandings of Pathogenesis" Encyclopedia, https://encyclopedia.pub/entry/42134 (accessed July 13, 2025).
Zorn, K.E., Cunningham, A.M., Meyer, A.E., Carlson, K.S., & Rao, S. (2023, March 13). Biological Understandings of Pathogenesis. In Encyclopedia. https://encyclopedia.pub/entry/42134
Zorn, Kristin E., et al. "Biological Understandings of Pathogenesis." Encyclopedia. Web. 13 March, 2023.
Biological Understandings of Pathogenesis
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This entry is adapted from the peer-reviewed paper 10.3390/cancers15051443

The biology underlying development of myeloid sarcomas (MS) remains poorly defined with no clear molecular determinants. Biological features such as cytogenetic changes, molecular abnormalities, and cell surface marker expression are not consistent across studies. Myeloid sarcomas (MS), commonly referred to as chloromas, are extramedullary tumors of acute myeloid leukemia (AML) with varying incidence and influence on outcomes. Pediatric MS has both a higher incidence and unique clinical presentation, cytogenetic profile, and set of risk factors compared to adult patients. The development of MS appears to require leukemia mobilization/release from the marrow environment, tissue invasion, and further changes leading to a tumor/mass phenotype.

myeloid sarcoma chloroma acute myeloid leukemia pediatric

1. CXCR4

CXCR4 (CXC chemokine receptor 4, CD184) is the receptor for the chemokine matrix cell derivative-1 (SDF-1/CXCL12) and is expressed by most tissues as well as hematopoietic stem cells and leukemic blasts wherein it facilitates the retention of hematopoietic stem cells in the bone marrow niche [1][2]. The CXCR4/SDF-1 axis may contribute to chemoresistance through downstream signaling cascade dysregulation within leukemia cells [1][3]. Higher CXCR4 expression has been seen in AML patients with extramedullary infiltration at diagnosis and extramedullary infiltration in childhood ALL [1][4]. The proposed mechanism of extramedullary involvement in acute leukemias is altered bone marrow homing and increased peripheral blood dissemination via a chemotactic gradient of SDF-1 with increased CXCR4 expression on the leukemia cells [5]. CXCR4/SDF-1 can promote the retention of AML cells within the skin of children with AML; however, CXCR4 expression by peripheral blood blasts was no different in patients with or without skin involvement [6]. Furthermore, a lack of association between SDF-1 polymorphisms and MS implies that small variants do not contribute to extramedullary disease development, although these have been previously of interest and described [7]. More common in adults, NPM1-mutated AML is associated with extramedullary disease and is associated with downregulation of CXCL12 and CXCR4 gene pathways [2].
While CXCR4 expression and signaling may be a contributing factor to extramedullary disease, its impact appears limited to initial release and migration of leukemia cells from the marrow and is not specific to MS development. Further work is needed to better characterize this mechanism and whether or how CXCR4 is contributing to discrete MS formation.

2. CD56

CD56 (also known as neural cell adhesion molecule-1 or NCAM1) is normally expressed by natural killer (NK) cells and other immune cell subtypes and is housed on chromosome 11q23.1. It is frequently described as part of the immunophenotype of AML with MS [8][9][10]. Expression patterns of CD56 are not consistently described, however, and in a population of adult t(8;21) AML patients, there was no association between CD56 expression and presence of extramedullary disease [11]. AML in adults with CD56 positivity is more commonly associated with worse 5-year EFS and OS; however, a report in low-risk patients shows no association with outcome [12][13][14]. Additionally, post-allo-HSCT CD56 positivity is not associated with extramedullary relapse [15]. Despite the frequent CD56+ immunophenotype, there is no described mechanism or in vitro data to suggest the significance of this finding. Additional experimental studies are required to determine if CD56 is simply a biomarker of MS or is required for MS development.

3. Integrins and Cell Adhesion Molecules (CAMs)

An AML-extracellular matrix interaction is likely critical to the development of MS. This is illustrated in transcriptome analysis of adult patient-derived AMLs demonstrating enrichment of cell surface gene sets in those AMLs with concomitant MS [16]. This includes integrin-α7 (ITGA7), which showed a higher expression in AML with associated MS in addition to high expression in MS samples [16]. Laminin 211 is a specific ligand of integrin-α7 that signals through the ERK signaling cascade [16]. While there is much described about the role of integrins and selectins in migration and homing of hematopoietic stem cells, there remains no clear mechanism by which these molecules facilitate MS formation [17][18]. Further study is needed to better evaluate the role of cell adhesion molecules in MS development and whether targeting these cell interactions may provide therapeutic benefit for patients with MS.

4. Vascular Endothelial Growth Factor (VEGF) and Receptor (VEGFR)

Angiogenesis plays a notable role in acute leukemia with increased microvascular density in AML and adult MS [19]. VEGFR2, the major mediator of the mitogenic, angiogenic, and permeability effects of VEGF, may contribute to the development of MS [20]. VEGF signaling via the PI3K/Akt pathway in the setting of hERG1 expression was necessary for an in vitro migratory phenotype in AML cells [21]. In adults, the small molecule VEGFR2 tyrosine kinase inhibitor apatinib (also known as TN968D1) demonstrated enhanced antileukemic effects in ex vivo cytotoxicity studies from patient-derived AML samples with associated extramedullary disease [22]. Angiogenesis is well-described in the pathogenesis of other malignancies and it is reasonable to think that a unique perturbation may play a role in the migration or tumor formation of MS.

5. Matrix Metalloproteinases (MMP)

In vitro studies have described the role of MMP secretion (MMP-2 and MMP-9) by leukemia cells contributing to invasion capacity, most notably of the blood-brain barrier, with upstream regulation by mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3-K)/AKT pathways [23][24]. Additionally, TIMP-2 (tissue inhibitor of metalloproteinase 2) upregulation has been seen with increased leukemia cell line (i.e., SHI-1) invasion both in vitro and in vivo with more extensive and severe extramedullary infiltration through both MMP-2-dependent and independent activities [25][26]. Other in vitro studies propose a role for the β2 integrin-proMMP-9 complex in the extramedullary phenotype of AML [27]. Type IV collagenase secretion enhanced by TNFα and TGFβ from a patient-derived MS cell line increased in vitro cell invasion with collagenase secretion demonstrated in the MS AML cell line but not other leukemia cell lines [28]. While tissue invasion by leukemia cells is likely required for MS development, not all of the critical players have been identified.

6. Epigenetic Dysregulation

Epigenetic dysregulation has been reported in the context of extramedullary disease and infiltration in AML. Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), which deposits Histone 3 Lysine 27 trimethylation (H3K27me3). High EZH2 expression is correlated with higher peripheral blood blast percentages as well as extramedullary infiltration in patients with AML with numerous well-established biological roles. In vitro studies suggest that migration of AML cells appears to be regulated by EZH2/p-ERK/p-cmyc/MMP-2 and E-cadherin signaling pathways [29]. EZH2 is a frequently mutated gene in AML; however, EZH2 has a variety of biologic influences and a unique role in MS formation remains undefined [30][31].
Altered DNA methylation is another described mechanism in the development of extramedullary disease with key enzymes frequently mutated in AML. DNA methyltransferase 3A (DNMT3A) mutations contribute to altered DNA methylation, subsequently resulting in increased expression of a subset of genes with specific roles in myeloproliferation and extramedullary hematopoiesis [32]. DNMT3A mutation appears to contribute to extramedullary CNS infiltration mediated by overexpression of TWIST1, a key epithelial mesenchymal transition transcription factor, which is not otherwise well described in AML [33]. Furthermore, TET2 is a member of the ten-eleven translocation (TET) gene family and is a key enzyme for DNA demethylation and a critical regulator for hematopoietic stem cell homeostasis. Models using TET2-deficient mice demonstrated not only high incidence of MS development but also transplant ability of the MS cells as well as an in vivo response to azacitidine treatment [34]. Decreased TET2 expression was also seen in patient-derived MS samples with further suggestion of methylation changes impacting MS development [35].
AML has many examples of mutations in epigenetic pathways that are enriched in AML more than many other disease entities and may not be directly related to their involvement in MS [31]. The role of epigenetic dysregulation in leukemia migration and invasion with described MS phenotypes is intriguing yet requires further study. Additional research may uncover future targetable pathways for MS treatment, and as noted below, case reports have demonstrated the safety and efficacy of hypomethylating agent use for patients with MS.

7. Other Biological Associations

Mesothelin (MSLN) is a cell surface protein hypothesized to be involved in cell adhesion and is overexpressed in a subset of AML patients. MSLN overexpression was strongly associated with KMT2A-R, t(8;21), and inv(16) as well as the presence of extramedullary disease in children and young adults with AML. Methylation profiling further demonstrated an inverse association between MSLN promoter methylation and MSLN expression, suggesting another impact of epigenetic dysregulation [36].
Versican (VCAN) overexpression in the setting of NPM1-mutated AML is associated with an invasive phenotype and higher expression levels in patients with skin infiltration [37]. Lysyl oxidase (LOX), which has roles in pediatric acute megakaryoblastic leukemia and in the creation of a growth permissive fibrotic microenvironment, was associated with increased extramedullary disease in adults with AML and high plasma LOX activity [38]. WT1 overexpression has also been described in MS cases as well as in extramedullary relapsed disease [39][40]. ERG transcription factor overexpression, similar to that of Ewing sarcoma, has been seen in patient-derived MS samples [41]. Multiple studies describe other associations observed in AML and extramedullary disease, including increased expression of amyloid precursor protein (APP) in AML1/ETO leukemia cells perhaps mediating the p-ERK/c-Myc/MMP-2 pathway, expression of miR-29c&b2, circular RNA expression patterns, and expression of CD25 and CD117 [42][43][44][45][46][47][48]. Polo-like kinase 1 (PLK1), which is involved in cell cycle control, was effectively inhibited in vivo using a patient-derived leukemia in mice with improvement in extramedullary disease [49]. PD-1 and PD-L1 have been investigated given the described efficacy of checkpoint inhibitors; however, there was no difference in expression of PD-1/PD-L1 in MS tested, and they may instead have more impact in the surrounding tumor microenvironment [50][51]. Using mouse models, others observe a maturation plasticity of leukemia cells, with potential implications for chemotherapy resistance as a mechanism for extramedullary relapse [52]. A PIM2/MYC co-expressed mouse model demonstrated consistent and lethal in vivo MS development with MYC expression likely contributing to the phenotype [53]. Mouse models have also demonstrated cooperation between MLL/AF10 and activating KRAS mutations, with increased cell adhesion properties contributing to in vivo MS formation via Adgra3 and Hoxa11 [54][55].
While many different mechanisms have been suggested in the development of MS, there remains no clear understanding of the pathogenesis. As such, it is hard to definitively identify the potential molecular determinants causing MS formation is some AML patients but not others. While the pathogenesis remains to be fully elucidated, prior studies suggest that there are likely multiple steps leading to MS development, including release from the bone marrow (which may be represented by higher WBC counts associated with MS), tissue invasion, and discrete mass formation, with the latter being the most consequential with regards to leukemia and the least described. Investigating how these different steps may cooperate and ultimately how the leukemia cells aggregate and sustain an aggregated phenotype requires dedicated study. Furthermore, the immune evasive or immunosuppressive microenvironment of MS illustrated in the post-allo-HSCT setting highlights that there is much more to learn about the pathogenesis of MS and its uniqueness with respect to its systemic/intramedullary AML counterpart.

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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Kristin E. Zorn
,
Ashley M. Cunningham
,
Alison E. Meyer
,
Karen Sue Carlson
,
Sridhar Rao
View Times: 513
Revisions: 2 times (View History)
Update Date: 14 Mar 2023
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