Date of Award

Spring 5-15-2019

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease, characterized by recurrent genetic mutations. Mutations in the cohesin complex are one of the 8 functional categories of mutations in AML. SMC3 encodes a subunit of the cohesin complex, which has important roles in chromosome segregation, genome instability, and gene expression. In the first chapter of the dissertation, we discuss the genetics of AML, normal functions of the cohesin complex, and the interplay between cohesin mutations and myeloid malignancies.

SMC3 is recurrently mutated in AML and other myeloid malignancies. In the second chapter of the dissertation, we compare the consequences of Smc3 deficient and haploinsufficient mouse models to determine whether the heterozygous missense mutations in SMC3 might have dominant-negative effects or phenocopy loss-of-function effects. We found that homozygous deletion of Smc3 during embryogenesis or in adult mice resulted in hematopoietic failure. SMC3 missense mutations are therefore unlikely to be associated with simple dominant negative phenotypes due to incompatibility with hematopoiesis. Smc3 haploinsufficiency, in contrast, was tolerated during embryonic and adult hematopoiesis. Under steady-state conditions, Smc3 haploinsufficiency did not alter colony forming capacity ex vivo and led to modest transcriptional and chromatin accessibility changes in Lin-cKit+ progenitor cells. However, following tamoxifen-induced deletion in competitive transplantations, we observed a significant hematopoietic competitive disadvantage in Smc3 haploinsufficient bone marrow cells across myeloid and lymphoid lineages and within the stem/progenitor compartments. The competitive disadvantage was not affected by different conditions of hematopoietic stresses, but was partially abrogated by concurrent Dnmt3a haploinsufficiency, suggesting that antecedent mutations may be the prerequisites to realize the leukemogenic potential of Smc3 mutations.

In the third chapter of the dissertation, we present a case of an older women that initially appeared to be treatment-related AML following non-cytotoxic all-trans retinoic acid (ATRA)/arsenic trioxide (ATO) therapy for acute promyelocytic leukemia (APL), but upon further analysis found to be more consistent with secondary AML. Exome sequencing revealed a TET2-mutated dominant clonal process that preceded the APL diagnosis, persisted, and gave rise to an AML-associated new subclone with a NPM1 mutation. Review of additional cytogenetic abnormalities observed in APL patients showed that cytogenetic abnormalities commonly occur as subclones of the APL clone, although one rare case with del(7) independent of the APL clone was identified. These results demonstrated that APL may emerge within the context of clonal hematopoiesis and caution must be exercised when interpreting the development of tAML after ATRA/ATO therapy, especially in older patients.

Language

English (en)

Chair and Committee

John S. Welch

Committee Members

Grant Challen, Timothy Ley, Matthew Walter, Katherine Weilbaecher,

Comments

Permanent URL: https://doi.org/10.7936/811y-e089

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