BCL2 is a proto-oncogene located at 18q21 that promotes B-cell survival via inhibition of apoptosis and confers chemotherapy resistance.

The BCL2 family includes both antiapoptotic and proapoptotic members that form heterodimers and homodimers.

Following death signals, proapoptotic homodimers alter mitochondrial membrane potential, trigger cytochrome c release, and caspase-mediated apoptosis.

Increased abundance of antiapoptotic BCL2 proteins favors the formation of antiapoptotic/proapoptotic heterodimers rather than proapoptotic/proapoptotic homodimers, limiting the effects of death signals at the mitochondrial membrane.

Either the relative excess of antiapoptotic BCL2 family members or the deficiency of proapoptotic isoforms may confer a survival advantage and contribute to lymphomagenesis.

BCL2 expression is normally down-regulated in the GC where apoptosis plays a critical role in negative B-cell selection.

Pathology

 BCL2 deregulation is most commonly associated with the t(14;18), present in approximately 15% of DLBCLs.

 BCL2 protein expression can be detected in approximately 50% of DLBCLs, independent of the t(14;18).

 Increased expression of the BCL2 protein is associated with an inferior outcome in DLBCL, though the t(14;18) alone has no predictive value.

 Because the t(14;18) is the hallmark abnormality in follicular lymphoma and transformed follicular lymphomas resemble de novo DLBCL, the reported frequencies of t(14;18) in DLBCL series may depend on how accurately included tumors and patients were prescreened.

Animal models

Proof of principle is provided by models in which mice overexpressing BCL2 protein developed follicular hyperplasia and extended survival of B lymphocytes; conversely, mice deficient for a proapoptotic BCL2 family member, BAD, developed DLBCL of GC origin.

Pathology

 IGH/BCL2 reaerangement by t(14;18)(q32;q21) in follicular B-cell lymphoma (70-80% of cases) (14q32 and 18q21)

References

 Abramson JS, Shipp MA. Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach. Blood. 2005 Aug 15;106(4):1164-74. PMID: #15855278#

 Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 2002 Sep;2(9):647-56. PMID: #12209154#