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Abstract
Although greater than 85% of inv(16) acute myeloid leukemia patients are able to achieve first complete remission after anthracycline- and cytarabine-based therapy, only about 60% of patients survive the disease long-term due to relapsed disease or treatment-related mortality. Multiple studies have shown that acute myeloid leukemia is composed of heterogeneous populations of leukemic clones that can exhibit a wide degree of genetic, epigenetic, and functional diversity, accounting for different outcomes in response to therapy. Genomic analysis of leukemic clones in paired diagnostic and relapse samples of acute myeloid leukemia has shown that all relapses stem from surviving leukemic or ancestral clones that acquire additional mutations allowing for renewed outgrowth. Since the majority of relapsed inv(16) patients are able to achieve a second complete remission with cytarabine-based salvage chemotherapy, most relapse cases are not due to mutations causing chemoresistance. Instead, these observations suggest a model where indolent subclones or refractory preleukemic cells serve as a reservoir for relapse. Therapeutic strategies that target residual leukemic cells could lead to more durable remissions, but are often complicated by difficulty in distinguishing them from normal hematopoietic stem/progenitor cells. Current therapeutic paradigms try to take advantage of specific early mutations that abnormally activate unique signaling pathways or produce fusion proteins that can be targeted. In inv(16) acute myeloid leukemia, the CBFβ-MYH11 fusion gene is the earliest known genetic lesion marking all leukemic and preleukemic cells. The work presented in the first part of this dissertation explores an immunophenotypic approach to targeting preleukemic and leukemic clones by showing that inv(16)+ cells can be segregated from residual normal hematopoietic stem/progenitor cells in the bone marrow by their expression of leukemia stem cell markers TIM3, CLL1, and CD33. The second part shows that a C-terminal domain in CBFβ-SMMHC fusion protein called the assembly competence domain is essential to inv(16) leukemogenesis and may represent a target for therapy.
