Transcriptional and Microenvironmental Regulation of Lineage Ambiguity in Leukemia

Abstract

Leukemia is characterized by the uncontrolled production of leukemic cells and impaired normal hematopoiesis. Although the combination of chemotherapies and hematopoietic stem cell transplantation has significantly improved the outcome of leukemia patients, a proportion of patients still suffer from relapse after treatment. Upon relapse, a phenomenon termed “lineage switch” is observed in a subset of leukemia patients, in which conversion of lymphoblastic leukemia to myeloid leukemia or vice versa is observed. A rare entity of leukemia called mixed-phenotype acute leukemia exhibits co-expression of markers representing two or three lineages. These two phenotypes regarding the lineage ambiguity suggest that the fate of some leukemia retain or acquire a certain degree of plasticity. Studies using animal models provide insight into how lineage specifying transcription factors can enforce or convert a fate in hematopoietic cells. Modeling lineage conversion in normal hematopoietic progenitor cells may improve our current understanding of how lineage switch occurs in leukemia. In this review, we will summarize the role of transcription factors and microenvironmental signals that confer fate plasticity to normal hematopoietic progenitor cells, and their potential to regulate lineage switching in leukemias. Future efforts to uncover the mechanisms contributing to lineage conversion in both normal hematopoiesis and leukemia may pave the way to improve current therapeutic strategies.

Fetal liver Mll-AF4+ hematopoietic stem and progenitor cells respond directly to poly(I:C), but not to a single maternal immune activation

“…MLL-AF4-driven leukemogenesis in mice appears to require additional factors to complete the transformation process. These factors could be cell intrinsic through the aberrant expression of a particular gene such as the reciprocal fusion AF4-MLL, but could also come from the microenvironment 25, 26, 27.…”

Pediatric Mixed-Phenotype Acute Leukemia: What’s New?

“…Lineage switch is a phenomenon in which a lymphoid leukemia converts to a myeloid leukemia (more common), but the opposite switch has also been reported [ 20 ]. This phenomenon is of particular interest in MPAL, is more commonly reported in KM2TA ( MLL )-rearranged leukemias, and often complicates management of these patients [ 21 ].…”

Regulation of Malignant Hematopoiesis by Bone Marrow Microenvironment

“…Similar to the normal hematopoietic system, stem or progenitor cells reside at the top of the hierarchy and produce descendant leukemic cells and self-renew to propagate leukemia and sustain clonal tumor burden ( 77 , 78 ). Although leukemia stem cell (LSC) seems to be less dependent on their niche than normal HSCs, the leukemogenic process does not completely abrogate niche dependence for LSCs.…”