It has long been known that cancers are largely driven by mutations and alterations in DNA. However, for the most part, cancer is not just the result of a single mutation. It is now well appreciated that different mutations can accumulate in cells, which, when combined, sometimes cause malignancy. However, on the way to becoming cancerous, cells with mutations are often in a precarious pre-cancerous state. Although it is not itself malignant, this state is characterized by expanded clonal populations and an increased likelihood of the development of full-blown disease. Because of the self-renewing nature of precursor hematopoietic cells, pre-leukemic mutations predisposing an individual to cancer can accumulate over time. Notably, many of these pre-cancerous cells are refractory to traditional treatments and can cause relapse even if all the other leukemic cells are killed in the first round of therapy.
To address to this issue, Ravi Majeti is studying patient-derived and CRISPR-engineered pre-leukemic hematopoietic stem cells (pHSCs) to explore their progression into acute myeloid leukemia (AML) and determine ways to kill them. To achieve these goals, his team is testing potential routes of eliminating pHSCs with existing chemotherapeutic drugs, evaluating the progression of pHSCs to AML using engineered mutations that have been found in patients’ pHSCs, and examining how the immune microenvironment affects progression to AML in different genetic backgrounds. These studies will lead to a better understanding of the cell populations responsible for AML relapse with the aim of targeting them with new cancer therapies.
PUBLISHED RESEARCH
Köhnke T, Majeti R. Clonal Hematopoiesis: From Mechanisms to Clinical Intervention. Cancer Discov. 2021.
Nakauchi Y, Azizi A, Thomas D, Corces MR, Reinisch A, Sharma R, Cruz Hernandez D, Kohnke T, Karigane D, Fan A, Martinez-Krams D, Stafford M, Kaur S, Dutta R, Phan P, Ediriwickrema A, McCarthy E, Ning Y, Phillips T, Ellison CK, Guler GD, Bergamaschi A, Ku CJ, Levy S, Majeti R. The cell type specific 5hmC landscape and dynamics of healthy human hematopoiesis and TET2-mutant pre-leukemia. Blood Cancer Discov. 2022.
Ediriwickrema A, Gentles AJ, Majeti R. Single-cell genomics in AML: extending the frontiers of AML research. Blood. 2023.
Köhnke T, Nuno KA, Alder CC, Gars EJ, Phan P, Fan AC, Majeti R. Human ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119. Blood Cancer Discov. 2024.
Landberg N, Köhnke T, Feng Y, Nakauchi Y, Fan AC, Linde MH, Karigane D, Lim K, Sinha R, Malcovati L, Thomas D, Majeti R. IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by inhibition of oxidative phosphorylation. Blood Cancer Discov. 2024.