Our findings substantiate and expand the spectrum of clinical presentations of perforin deficiency, linking PRF1 missense mutations to lymphoma susceptibility and highlighting clinical variability within families.
Mutations of its gene, PRF1, cause familial hemophagocytic lymphohistiocytosis but have also been associated with lymphomas and the autoimmune/lymphoproliferative syndrome.
Here we show that mice heterozygous for a targeted null mutation of Blm, the murine homolog of BLM, develop lymphoma earlier than wild-type littermates in response to challenge with murine leukemia virus and develop twice the number of intestinal tumors when crossed with mice carrying a mutation in the Apc tumor suppressor.
Patients with abdominal nodal disease had inferior lymphoma specific survival (p=0.04) and presented with higher age adjusted IPI (p<0.001), lactate dehydrogenase (p<0.001) and more often advanced stage (p<0.001), bulky disease (p<0.001), B-symptoms (p<0.001), and double expression of MYC and BCL2 (p=0.02) compared to patients without nodal abdominal involvement, but less often extranodal involvement (p<0.02).
New targeted therapies for hematological malignancy include chimeric antigen receptor T cells (CAR T cells), Bi-specific T-cell Engager (BiTE) blinatumomab, and the antibody-drug conjugate (ADC) of calicheamicin inotuzumab ozogamicin for acute lymphoblasic leukemia (ALL) and lymphoma; the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and phosphatidylinositol 3-kinase (PI3Kδ) inhibitor idelalisib for lymphoma and graft-versus-host disease (GVHD); FMS-like tyrosine kinase 3 (FLT3) inhibitors, such as midostaurin, sorafenib and gilteritinib for acute myeloid leukemia (AML); and the BCL-2 inhibitor venetoclax for a range of hematological malignancies including lymphoma and leukemia.
Overexpression and gain-of-function mutations in EZH2 are regarded as oncogenic drivers in lymphoma and other malignancies due to the silencing of tumor suppressors and differentiation genes.
Enhancer of zeste homolog 2 (EZH2) and Bcl-2 gene rearrangement or protein upregulation played pivotal roles in the carcinogenesis of various malignancies including lymphomas.
Aggressive lymphomas with MYC and BCL2 and/or BCL6 translocations ("double hit" lymphomas, DHL) represent a distinct diagnostic category in the updated World Health Organization (WHO) classification.
Notably, Rac1 expression, and its interaction with Bcl-2, positively correlate with S70pBcl-2 levels in patient-derived lymphoma tissues and with advanced stage lymphoma and melanoma.
Enhancer of zeste homolog 2 (EZH2), an H3K27-specific histone methyltransferase, has been shown to be frequently overexpressed in various human cancers including lymphoma.
The expression levels of MMP-9 and Bcl-2 were correlated with the body weight loss degree of mice, and the expression of MMP-9 was positively associated with that of BCL-2 in lymphomas.
However, no associations were found between DAPK methylation and clinicopathological features of lymphoma, in relation to gender (OR = 1.07, 95% CI (0.72, 1.59), P = 0.751), age (OR = 1.01, 95% CI (0.66, 1.55), P = 0.974), international prognostic index (OR = 1.20, 95% CI (0.63, 2.27), P = 0.575), B symptoms (OR = 0.76, 95% CI (0.38, 1.51), P = 0.452), serum lactate dehydrogenase (OR = 1.13, 95% CI (0.62, 2.05), P = 0.683), and BCL-2 expression (OR = 1.55, 95% CI (0.91, 2.66), P = 0.106).