Concise review: Blood relatives: formation and regulation of hematopoietic stem cells by the basic helix-loop-helix transcription factors stem cell leukemia and lymphoblastic leukemia-derived sequence 1.

The basic helix-loop-helix (bHLH) proteins are a large family of transcription factors that regulate the formation and fate of tissue stem cells. In hematopoiesis, the two major bHLH factors are stem cell leukemia (SCL) and lymphoblastic leukemia-derived sequence 1 (LYL1), both identified more than 20 years ago in chromosomal translocations occurring in T-cell acute lymphoblastic leukemia. SCL was termed the master regulator of hematopoiesis following the observation that SCL knockout mice die from complete lack of blood formation. However, once established, SCL is no longer required for maintenance of hematopoiesis. Pull-down experiments together with add-back experiments in SCL-null embryonic stem cells and generation of mice carrying a germline DNA binding mutation of SCL demonstrates that most of SCL function is mediated through the formation of a large DNA binding multiprotein complex with both repressor and activator potential. Recent genome-wide binding studies in a hematopoietic stem progenitor cell line suggest that SCL and LYL1 preferentially bind target DNA sequences as components of a heptad of transcription factors. LYL1, a paralog of SCL has been the forgotten sibling until recent mouse studies demonstrated that LYL1 replaced the function of SCL in adult hematopoiesis. Why LYL1 can replace the function of SCL for the maintenance but not formation of hematopoiesis remains a fundamental question. This review will compare and contrast the roles of these two transcription factors in hematopoiesis focusing on recent functional and genome-wide binding studies.