Scientists make a BID towards understanding chronic myelomonocytic leukemia

January 14, 2003

A collaboration of scientists from Harvard Medical School has discovered that mice lacking a gene called Bid develop the murine equivalent of human chronic myelomonocytic leukemia. As published in Genes & Development, this finding by Dr. Stanley Korsmeyer and colleagues demonstrates that the pro-apoptotic BID protein functions as a tumor suppressor, helping to maintain the delicate balance between cell survival and cell death in the bone marrow.

BID is a member of the BCL-2 protein family - a group of related, evolutionarily conserved proteins involved in the regulation of apoptosis, or programmed cell death. The BCL-2 protein family has both pro-apoptotic and anti-apoptotic members, which are classified by the presence of one or more of four structural domains, called BCL-2 homolgy domains (BH1-4). Previous work has shown that BID contains a BH3 domain and promotes apoptosis by acting as a liaison between death receptors at the cell surface and the intracellular apoptotic machinery.

Using mice genetically engineered to lack BID, Dr. Korsmeyer and colleagues demonstrated that BID is required for apoptosis -- and thus the overall homeostasis -- of myeloid (bone marrow-derived) cells. BID-deficient mice experienced an overexpansion of myeloid cells (myeloid hyperplasia) and ultimately succumbed to a form of leukemia closely resembling human chronic myelomonocytic leukemia (CMML). In fact, by 27 months of age, 73% of BID-deficient mice developed CMML.

Human CMML generally affects older adults, but it can also occur in childhood. It is characterized by the uncontrolled proliferation of a specific type of white blood cell, called a myelomonocyte (a white blood cell that has properties of both a monocyte and a granulocyte). The overabundance of myelomonocytes in the bone marrow of CMML patients crowds out and destroys other, normal blood cells, like red blood cells and platelets. Over time, such alterations in the cellular landscape of CMML patients' bone marrow causes paleness, bruising, bleeding, and ultimately - without treatment - death.

This discovery by Dr. Korsmeyer and colleagues not only posits BID as a possible genetic culprit in human CMML, but it also highlights potential roles for other BH3-only proteins in tumor suppression and human disease.

Cold Spring Harbor Laboratory

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