Sanbox:HL
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Pathophysiology
- The main pathological feature of Hogkin's lymphoma is the Reed-Sternberg cells which is created mainly due to activation of the nuclear factor kappa B (NF-kB) transcription factor-signaling pathway. The improper activation of the (NF-kB) system proteins is correlated with many neoplasms.[1][2]
- NF-kB is degraded normally by "I kappa B (IkB)" family in order to prevent the unwanted stimulation and neoplasm formation. However, there are specific cellular proteins which lead to inactivation of the (IkB). So, by inactivating the (IkB), the NF-kB transcription factors will not be degraded and leads to gene transcriptions activation.[1]
- In Hodgkin's lymphoma, there are elevated levels of the NF-kB proteins especially c-REL and REL-A.[3]
- Unstopped activation of (NF-kB):
- Active (NF-kB) will lead to consistent gene activation and eventually no apoptosis takes place. Moreover, uninhibited proliferation of Reed-Sterburg cells.
- Activation of (NF-kB) occurs due to the following causes:[4][5]
- Loss of function Mutation of the IkB protein which is responsible for inhibiting NF-kB
- Alteration in the NF-kB itself protecting it from inhibition by IkB
- Gain of function mutation of the MAP3K14 gene which is an activator of NF-kB
- NF-kB leads to activation of many genes which appear to be related to HL. Some examples of the genes expressed in HL include the following:[6]
- (ICAM-1) gene
- GM-CSF gene
- IL-6 gene
- IKBA gene
- Besides NF-kB signaling pathway, Hodgkin's lymphoma can be caused by mutations in JAK-STAT pathway. Alterations in JAK tyrosine kinases signaling lead to high levels of activated STAT pathway which is considered an observed feature in some cases of HL.[7]
References
- ↑ 1.0 1.1 Shishodia S, Aggarwal BB (2004). "Nuclear factor-kappaB activation mediates cellular transformation, proliferation, invasion angiogenesis and metastasis of cancer". Cancer Treat Res. 119: 139–73. PMID 15164877.
- ↑ Bargou RC, Leng C, Krappmann D, Emmerich F, Mapara MY, Bommert K; et al. (1996). "High-level nuclear NF-kappa B and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells". Blood. 87 (10): 4340–7. PMID 8639794.
- ↑ Ghosh S, May MJ, Kopp EB (1998). "NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses". Annu Rev Immunol. 16: 225–60. doi:10.1146/annurev.immunol.16.1.225. PMID 9597130.
- ↑ Joos S, Menz CK, Wrobel G, Siebert R, Gesk S, Ohl S; et al. (2002). "Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2". Blood. 99 (4): 1381–7. PMID 11830490.
- ↑ Mathas S, Hartmann S, Küppers R (2016). "Hodgkin lymphoma: Pathology and biology". Semin Hematol. 53 (3): 139–47. doi:10.1053/j.seminhematol.2016.05.007. PMID 27496304.
- ↑ Buri C, Körner M, Schärli P, Cefai D, Uguccioni M, Mueller C; et al. (2001). "CC chemokines and the receptors CCR3 and CCR5 are differentially expressed in the nonneoplastic leukocytic infiltrates of Hodgkin disease". Blood. 97 (6): 1543–8. PMID 11238088.
- ↑ Zahn M, Marienfeld R, Melzner I, Heinrich J, Renner B, Wegener S; et al. (2017). "A novel PTPN1 splice variant upregulates JAK/STAT activity in classical Hodgkin lymphoma cells". Blood. 129 (11): 1480–1490. doi:10.1182/blood-2016-06-720516. PMID 28082443.