PMLBCL : JAK-STAT Signaling Cascade

Image 10 of 21

Image Description

JAK-STAT Signaling Cascade: This is another major pathway regulating cell proliferation that is altered in primary mediastinal large B-cell lymphomas (PMLBCL). It is activated by interleukin (IL) receptors, mainly IL-4 and IL-13. Amplification of 9p24.1 region on chromosome 9 (containing genes encoding JAK2, PDL1 & PDL2) has been found in approximately 63% of PMLBCL cases. This correlates with JAK2 overexpression and JAK-STAT cascade activation. It results in constitutive expression of several key genes required to initiate and/or maintain malignant transformation.

Overexpression of PDL1 and PDL2 leads to an exhaustion of T-cells and helps tumor cells escape from immunosurveillance. Whole transcriptome studies have shown alterations in several negative regulators of JAK-STAT pathway, such as SOCS1 and PTPN1. Another mechanism is upregulation of STAT6 due to an activating point mutation (36% of PMLBCL cases). These alterations cause JAK-STAT cascade activation and cell proliferation.

Image source: Bose, S. et al. Targeting the JAK/STAT Signaling Pathway Using Phytocompounds for Cancer Prevention and Therapy. Cells 2020, 9, 1451. Used under: Creative Commons Attribution License.

About the Disease

Primary mediastinal large B-cell lymphoma (PMLBCL) is a rare, aggressive, distinct subtype of large B-cell lymphoma localized in anterosuperior mediastinum. It shares clinical, morphologic, and molecular genetic features with nodular sclerosing Hodgkin lymphoma. It makes up 2-3% of non-Hodgkin lymphomas and affects young adults with a female predilection. Patients develop compressive symptoms, such as cough and dyspnea, from the rapidly growing mediastinal mass. About 20-30% have superior vena cava syndrome. Pleural and pericardial effusion develop in 30-50%. Surrounding thoracic structures may be invaded. Bone marrow is rarely involved. Extranodal sites may be invaded in advanced stages. The tumor cells are highly variable, medium-to-large size, with irregular or multilobated nuclei and pale or clear cytoplasm in a sclerotic stroma. Reed-Sternberg-like cells may be present. Immunophenotype: positive for pan B-cell antigens (CD19, CD20, CD22, CD79a), no surface or cytoplasmic immunoglobulins, PDL1+, PDL2+, PAX5%, CD30+ (variable, heterogenous), IRF4/MUM1+, BCL2, BCL6, PU.1, OCT2; variable positivity for CD15, CD10, CD11c, CD23, MYC; negative for EBV. MAL gene (chromosome 2q) is + in 70%. Ig heavy and light chain genes are clonally rearranged. TCR genes are germline. Rearrangements of CCND1, BCL2, BCL6, and MYC are rare/absent. Three molecular pathways are implicated in the pathogenesis - NF-κB signaling pathway, JAK-STAT signaling cascade, and immune privilege. References:Dabrowska-Iwanicka A & Walewski J. Primary Mediastinal Large B-cell Lymphoma. Curr Hematol Malig Rep (2014) 9:273-283. Lees, C. et al. Biology and therapy of primary mediastinal B-cell lymphoma : current status and future directions. British Journal of Haematology, 2019, 185, 25-41. Jaffe, E. S. et al (2017). Hematopathology - Second Edition. Philadelphia, PA. Elsevier. Swerdlow, S. H. et al (2017). WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, Revised 4th Edition; IARC, Lyon, France.

Image 10 of 21