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IntroductionHematopoiesis is maintained by a pool of hematopoietic stem cells (HSCs) defined by their capacity to self-renew and, hence, to maintain the pool and to differentiate into all mature progenies. These properties underlie their ability to reconstitute the hematopoietic system. 1 HSCs are identified by molecular markers 2 and are divided into long-term HSCs (LT-HSCs), short-term HSCs (STHSCs), and multilineage progenitors (MPPs). 3,4 As they differentiate, HSCs give rise to committed progenitors, such as common lymphoid progenitors (CLPs) or common myeloid progenitors (CMPs), which generate mature cells within the different hematopoietic lineages. 5 The action of HSCs to self-renew or to differentiate is a tightly controlled process linked to the induction or repression of some crucial genes. 6 Gene-targeting experiments have provided support to this hypothesis by identifying transcription factors of various families or their coregulators that are implicated in HSC biology. 7,8 The basic helix-loop-helix (bHLH) family of transcription factors regulates a wide range of developmental events. 1,9 Some bHLHs, such as MyoD and NeuroD, display restricted tissue expression and control the differentiation of particular cellular lineages. 10 They form transactivating dimers by heteromerization with ubiquitous bHLH proteins, termed E proteins, such as E2A, E12, and E47 genes. 11,12 Conversely, the latter proteins are repressed by other HLH proteins, which often precludes differentiation. 10,13,14 The tal/scl gene (hereafter referred to as scl) encodes a bHLH protein. 15,16 It was identified through its implication in T-cell acute lymphocytic leukemia (T-ALL). Knock-out (KO) experiments 17,18 show that scl is autonomously required for primitive and definitive hematopoiesis. 19,20 Moreover, its enforced expression enhances megakaryocytopoiesis and erythropoiesis. 21,22 The Lyl-1 gene encodes a bHLH protein closely related to scl. 23 Its transcriptional activation upon translocation is also associated with T-ALL. 24 SCL and LYL-1 bHLH regions show 82% of amino acid identity, 24 suggesting that these 2 proteins share at least some target genes and biologic functions. 25,26 However, LYL-1 and SCL diverge largely outside the bHLH region and display a distinct expression pattern in hematopoietic cells. 23,27 From the Insitut National de la The biologic functions of SCL prompted us to investigate those of LYL-1 in hematopoiesis. In contrast to scl Ϫ/Ϫ mice, Lyl-1 Ϫ/Ϫ mice do not exhibit embryonic lethality but have a reduced number of B cells. Although the CLP compartment is normal, the immature B-cell compartments are reduced in adult mice. In addition, we show that Lyl-1 is highly expressed in stem/progenitor cells, correlating with an important role in the control of the size and function of this cell compartment. Similarly, the number of multipotent progenitor S 12 colony-forming units (CFU-S 12 s) is reduced in Lyl-1 Ϫ/Ϫ animals. Overall, these defects are distinct from those revealed upon scl KO, suggesting that...