Human Genetics and Hematology

Dr. Arleen Auerbach
Clinical Geneticist

Dr. Auerbach's research has focused on Fanconi anemia (FA), a genetically heterogeneous recessively inherited syndrome characterized by developmental abnormalities, life-threatening bone-marrow failure and predisposition to a variety of cancers, particularly acute myelogenous leukemia and squamous cell carcinomas. Researchers who study Fanconi anemia have access to a large number of patients with diverse features of this rare disease. These patients are available through the International Fanconi Anemia Registry (IFAR), which is maintained at Rockefeller. The IFAR aims to elucidate clinical and genetic features in Fanconi anemia to better define this heterogeneous disorder and differentiate it from other syndromes with overlapping features (see 2008 IFAR poster). In addition, Auerbach is the curator for the "Locus Specific Database" (LSDB) for Fanconi anemia, a compendium of all known genetic variants associated with pathology in Fanconi patients (http://www.rockefeller.edu/fanconi/mutate/).

Although the pathophysiology of Fanconi anemia is not understood, research in Dr. Auerbach's work has demonstrated that hypersensitivity to the DNA cross-linking agent diepoxybutane can be used as a cellular marker for the disease, facilitating prenatal as well as postnatal diagnosis. The work on the prenatal diagnosis of Fanconi anemia played a major role in the use of this syndrome as a model for the development of umbilical cord blood transplantation as an alternative to bone marrow transplantation in the treatment of hematologic disorders. The first human cord blood transplant was in a Fanconi patient in 1988; the patient is still alive and well after 20 years. This methodology is now being applied for preimplantation genetic diagnosis (PGD)/in vitro fertilization (IVF). Currently, with private funding in collaboration with the Brivanlou laboratory, embryos identified as affected with Fanconi anemia after PGD/IVF are used as a source of cells for the derivation and study of Fanconi human embryonic stem cell lines (HESCs). We expect that genome wide and comparative embryological approaches using modern molecular tools may further understanding of the developmental abnormalities, bone marrow failure, and a predisposition to malignancy in FA patients.

As part of a consortium effort, Dr. Auerbach and her colleagues identified the gene for complementation group A (FANCA), which accounts for 65 percent of Fanconi anemia cases. More recently Dr. Auerbach and her colleagues have played a major role in the identification of FANCJ/BRIP1, FANCN/PALB2 and FANCI. Current research focuses on identification of additional genes that cause Fanconi anemia, as there are still IFAR patients for whom all known Fanconi genes have been ruled out.

The Fanconi anemia genes all encode unique proteins, most of which do not exhibit any known functional domains; these may thus represent a new class of genes associated with the maintenance of genomic stability. Among the thirteen Fanconi proteins that have been identified, BRCA2 (FANCD1), PALB2 and BRIP1 are known to predispose heterozygous carriers to breast cancer. Through the IFAR, Dr. Auerbach's lab has obtained tissue samples and established cell lines from over 600 subjects with various Fanconi anemia subtypes. This cell repository should be very valuable for future studies to understand the role of the Fanconi genes in the cancer.