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).
Thus, constitutive IP<sub>3</sub> signaling in lymphoma and leukemia cells is not only important for cancer cell survival, but also represents a vulnerability, rendering cancer cells dependent on Bcl-2 to limit IP<sub>3</sub>R activity.
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).
We identified 122 patients diagnosed as having large B-cell lymphoma (44, MYC-negative; 29, MYC-EC; 23, MYC rearrangement; 22, MYC and BCL2 rearrangements; 4, MYC, BCL2, and BCL6 rearrangements). p53 expression significantly correlated with DLBCL with abnormal MYC status (MYC-EC, MYC rearrangement, and MYC overexpression), but adverse p53 prognostic effect was only seen with MYC-rearranged lymphoma.
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.
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.
Overexpression of the pro-survival member BCL-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukemia.
The mRNA and protein expression levels of B cell leukemia/lymphoma (Bcl‑2), Bcl‑2 associated X (Bax), cyclin dependent kinase 4 (CDK4), cyclin D1 and p21 were evaluated using reverse transcription‑polymerase chain reaction and western blot analysis, respectively.
Some cytokines and proteins associated with cell survival and proliferation, such as BAFF, APRIL, IL6 and BCL2, have been found to be elevated both in SLE and lymphoma.
Mef2b<sup>D83V</sup> expression in mice leads to GC enlargement and lymphoma development, a phenotype that becomes fully penetrant in combination with BCL2 de-regulation, an event associated with human MEF2B mutations.
As bcl-2 proteins, cyclin dependent kinases (CDK) and phosphoinositol-3- kinase (PI3K) also influence mitochondrial physiology and metabolism with clear relevance to the pathogenesis of lymphoma, we investigated the potentiating effects of metformin when combined with novel agents Venetoclax (bcl-2 inhibitor), BAY-1143572 (CDK9 inhibitor) and Idelalisib (p110δ- PI3K inhibitor).
In order to gain a more comprehensive insight into the nature of venetoclax resistance mechanisms, we evaluated the changes in the BCL-2 family members at the genetic and expression levels in seven different venetoclax-resistant derived leukemia and lymphoma cell lines.
Moreover, CCl4-induced apoptosis in the mouse liver was inhibited by hSAP, as measured by terminal-deoxynucleotidyl transferase mediated nick-end labeling (TUNEL) assay and cleaved caspase-3 expression. hSAP significantly restored the expression of B cell lymphoma/leukemia (Bcl)-2 and suppressed the expression of Bcl-2-associated X protein (Bax) in vivo.
There were 47 DTHLs, 36 cases with MYC and BCL2 and/or BCL6 extra signals (ES) and/or rearrangements (ES group, excludes DTHLs), 9 with MYC rearrangements only (single-hit lymphoma), and 95 with no MYC abnormalities (NM).
A distinctive form of diffuse large B-cell lymphoma is the double-hit lymphoma, with most cases exhibiting a combined MYC and BCL2 rearrangement, leading some hematopathologists to propose the term MYC/BCL2lymphoma.
He trained in oncology at St Bartholomew's Hospital, London, where he was an Imperial Cancer Research Fund (ICRF) Clinical Research Fellow and completed his doctoral research on the Bcl-2 gene, its potential as a therapeutic target in lymphoma and the effects of CD40 ligation on the B-cell surface.
Most of the refractory patients exhibit double-hit lymphoma (MYC-BCL2 rearrangement) or double-protein-expression lymphoma (MYC-BCL2 hyperexpression) which have a more aggressive clinical picture.