Joint Fellowship Training Program
Mentor:
Gerald E Marti, M.D., Ph.D.
Organizational Affiliation and Position:
Medical Officer and Research-Regulatory Scientist, Cellular
and Tissue Therapy Branch, Division of Cellular and Gene Therapies, Center
for Biologis Evaluation and Research (CBER), FDA
Email:
gerald.marti@fda.hhs.gov
gemarti@helix.nih.gov
Phone:
(301)-827-0453
Running Title of Program:
Studies of MBL in familial chronic lymphocytic leukemia (CLL)
Research Project Summary:
CLL is the most common adult hematological malignancy in the United States
and shows the highest tendency to form familial clusters. In an
aging US population, a better understanding of CLL in the elderly would be
a public health benefit. The early molecular lesions in CLL
remain unknown. Monoclonal B cell lymphocytosis (MBL) is thought to be a precursor
state for CLL and could be a useful surrogate marker for the early detection
of CLL. It is seen in unaffected first-degree relatives in familial CLL,
in individuals living in toxic waste sites and in aging. We studied MBL using
multicolor flow cytometry (FCM) and defined a novel B cell subset in these
subjects. Single cell PCR studies of the B cell repertoire of FDR individuals
with MBL suggest the presence of intra-clonal heterogeneity. We have
also explored the use of quantitative FCM to evaluate the ZAP-70 and CD38 surrogate
markers for aggressive CLL. We have also developed a NZB murine model for human
CLL where the syntenic 13q14 region shows a mutation in the microRNA cluster
containing Mir16-1. The analogous microRNA mutation is found in sporadic
human CLL.
Proposed project for IOTF fellow:
The IOTF fellow will be able to chose a project in one of three areas: (1)
Multicolor QFCM and sorting of MBL B cell subsets in familial CLL; (2) Separation
of diploid and anueploid mouse tumor cells to define murine MBL; (3) Multicolor
analysis of ZAP-70 and CD38 in a B cell panel. Ig gene sequencing is
ongoing for MBL and the molecular screening of the microRNA abnormalities are
being developed to provide for a functional assay for human CLL defect.
Regulatory Activity:
The Fellow will review applications of in vitro diagnostics
(IVDs) and cellular therapies, the 510(k) or IND review process. The fellow
will gradually accumulate experience and spend up to 50% of their time in reviewing
manufacturing, production, and characterization of cell therapy products or
IVDs. There will also be an emphasis on standards for clinical flow cyotometry. M.D.s
can also spend a portion of their time learning and performing clinical reviews
within the clinical/pharmacology/toxicology review division.
Reference(s):
Marti et al, Overview of Monoclonal B Cell Lymphocytosis; 2007 BJH, 139, 701-708.
Abbasi et al, B Cell Repertoire and Clonal Analysis in Unaffected First Degree
Relatives in Familial CLL Kindred, 2007 BJH, 139, 820–82.
Raveche et al, Abnormal microRNA-16 Locus with Synteny to Human 13q14 Linked
to CLL in NZB Mice (Blood. 2007;109:5079-5086).
Wang, et al, Toward Quantitative Fluorescence Measurements with Multicolored
Flow Cytometry; Cytometry Dec 2007, Published online Dec 28, 2007.
