Shared roles for Scl and Lyl1 in murine platelet production and function.

The stem cell leukemia (Scl or Tal1) protein forms part of a multimeric transcription factor complex required for normal megakaryopoiesis. However, unlike other members of this complex such as Gata1, Fli1, and Runx1, mutations of Scl have not been observed as a cause of inherited thrombocytopenia. We postulated that functional redundancy with its closely related family member, lymphoblastic leukemia 1 (Lyl1) might explain this observation. To determine whether Lyl1 can substitute for Scl in megakaryopoiesis, we examined the platelet phenotype of mice lacking 1 or both factors in megakaryocytes. Conditional Scl knockout (KO) mice crossed with transgenic mice expressing Cre recombinase under the control of the mouse platelet factor 4 (Pf4) promoter generated megakaryocytes with markedly reduced but not absent Scl These Pf4Sclc-KO mice had mild thrombocytopenia and subtle defects in platelet aggregation. However, Pf4Sclc-KO mice generated on an Lyl1-null background (double knockout [DKO] mice) had severe macrothrombocytopenia, abnormal megakaryocyte morphology, defective pro-platelet formation, and markedly impaired platelet aggregation. DKO megakaryocytes, but not single-knockout megakaryocytes, had reduced expression of Gata1, Fli1, Nfe2, and many other genes that cause inherited thrombocytopenia. These gene expression changes were significantly associated with shared Scl and Lyl1 E-box binding sites that were also enriched for Gata1, Ets, and Runx1 motifs. Thus, Scl and Lyl1 share functional roles in platelet production by regulating expression of partner proteins including Gata1. We propose that this functional redundancy provides one explanation for the absence of Scl and Lyl1 mutations in inherited thrombocytopenia.

Oncogenic transcriptional program driven by TAL1 in T-cell acute lymphoblastic leukemia.

TAL1/SCL is a prime example of an oncogenic transcription factor that is abnormally expressed in acute leukemia due to the replacement of regulator elements. This gene has also been recognized as an essential regulator of hematopoiesis. TAL1 expression is strictly regulated in a lineage- and stage-specific manner. Such precise control is crucial for the switching of the transcriptional program. The misexpression of TAL1 in immature thymocytes leads to a widespread series of orchestrated downstream events that affect several different cellular machineries, resulting in a lethal consequence, namely T-cell acute lymphoblastic leukemia (T-ALL). In this article, we will discuss the transcriptional regulatory network and downstream target genes, including protein-coding genes and non-coding RNAs, controlled by TAL1 in normal hematopoiesis and T-cell leukemogenesis.

Specification of neurotransmitter identity by Tal1 in thalamic nuclei.

BACKGROUND: The neurons contributing to thalamic nuclei are derived from at least two distinct progenitor domains: the caudal (cTH) and rostral (rTH) populations of thalamic progenitors. These neural compartments exhibit unique neurogenic patterns, and the molecular mechanisms underlying the acquisition of neurotransmitter identity remain largely unclear. RESULTS: T-cell acute lymphocytic leukemia protein 1 (Tal1) was expressed in the early postmitotic cells in the rTH domain, and its expression was maintained in mature thalamic neurons in the ventrolateral geniculate nucleus (vLG) and the intergeniculate leaflet (IGL). To investigate a role of Tal1 in thalamic development, we used a newly generated mouse line driving Cre-mediated recombination in the rTH domain. Conditional deletion of Tal1 did not alter regional patterning in the developing diencephalon. However, in the absence of Tal1, rTH-derived thalamic neurons failed to maintain their postmitotic neuronal features, including neurotransmitter profile. Tal1-deficient thalamic neurons lost their GABAergic markers such as Gad1, Npy, and Penk in IGL/vLG. These defects may be associated at least in part with down-regulation of Nkx2.2, which is known as a critical regulator of rTH-derived GABAergic neurons. CONCLUSIONS: Our results demonstrate that Tal1 plays an essential role in regulating neurotransmitter phenotype in the developing thalamic nuclei. Developmental Dynamics 246:749-758, 2017. © 2017 Wiley Periodicals, Inc.