Nonrandom chromosomal abnormalities are associated with multiple hematologic malignancies. The molecular characterization of the abnormalities such as the classic t(8,14) in Burkitt's lymphoma, the t(9,22) Philadelphia chromosome in chronic myelogenous leukemia, and the t(1,19) in some cases of acute lymphoblastic leukemia have suggested mechanisms of disease. Although multiple cytogenetic derangements are associated with acute myelogenous leukemia (AML), molecular delineation of these abnormalities has not been accomplished. This project will define on a molecular level the breakpoints of the inversion of chromosome 16 (inv16(p13;q22)) found in the myelomonocytic subtype of AML associated with marrow eosinophilia (AML-M4Eo). Patients with AML-M4Eo often develop central nervous system disease and may have a better prognosis than is typical for AML. This clinical-pathologic-cytogenetic syndrome suggests a consistent molecular breakpoint. Phase I will localize the breakpoint within several hundred kilobases using two complementary strategies. Underway is pulse-field gel electrophoresis (PFGE) of dna from leukemic and normal samples probed with relevant regions of chromosome 16 to identify rearrangements and allow comparison among multiple leukemic specimens. The second strategy utilizes chromosomal jumping. Libraries of both leukemic and normal dna will be jumped in parallel beginning in the region known to be near the breakpoint by cytogenetic analysis. sequential jumps will yield clear differences when the breakpoint is reached and findings will then be confirmed on the multiple samples prepared for PFGE. Phase II will precisely define the regions of the breakpoints using the probes isolated in phase I. Long-range mapping, isolation of active transcriptional units, screening of appropriate libraries, and chromosomal walking will identify the normal genes altered by this inversion. At the completion of the project, the applicant will be equipped for a career as an academic physician scientist.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Physician Scientist Award (K11)
Project #
1K11CA001602-01
Application #
3085926
Study Section
Cancer Institutional Fellowship Review Committee (CT)
Project Start
1991-09-30
Project End
1996-09-29
Budget Start
1991-09-30
Budget End
1992-09-29
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215