Research

Leukemia early evolution

Leukemia is bone marrow failure due to the outgrowth of clonal cells. Patients will present to the clinic with bone marrow failure, however the disease starts many years before that. A preleukemic phase that precedes bone marrow failure can be identified in most cases of leukemia. In the preleukemic phase stem/progenitor cells acquire recurrent mutations which lead to clonal hematopoiesis. Many individuals will develop clonal hematopoiesis but not all will develop leukemia in their life time. Understanding the rules of human leukemia evolution by in depth analysis of single cell phylogenetics is one of the ways we try to understand leukemia evolution.

The functional consequences of preleukemic mutations

Our original work (Shlush et.al Nature 2014) identified high mutant allele frequencies of preleukemic mutations in mature myeloid cells among AML patients in long term remission. This observation suggests that in some cases almost the entire monocyte/macrophage/neutrophil population can be derived from a preleukemic progenitor. The functional consequences of the mutations on mature myeloid cells is of great interest, as observations in elderly suggest that one of the major cause of death in the elderly is infection due to myeloid dysfunction. In our lab we follow healthy individuals with preleukemic mutations to try and learn their functional consequences.

The changing environment

The human bone marrow macro-environment is constantly changing. At the age of twenty these changes become apparent as MRI studies demonstrate a transition from a red marrow (rich in blood vessels) to a yellow marrow (rich in fat). Why this changes occur and how they are related to the other phenotype of the aged marrow is unclear. Reduced diversity of B and T cell repertoire is another change in the environment and its role in shaping the evolution of the rest of the hematopoietic system is also unclear. Studying the interaction between the changing environment and preleukemic hematopoiesis is another focus of our lab.