Oncogenic transcription factors, from hematopoietic stem cells to thymocyte reprogramming

Abstract

Normal hematopoietic stem cells (HSCs) are uniquely endowed with long term self-renewal capacities to sustain blood cell production throughout life whereas progenitors and mature blood cells have finite life spans. HSCs normally reside in the protective microenvironment of the bone marrow where they remain dormant. These cells divide infrequently to produce mature hematopoietic cells without compromising the pool of HSCs. Our results indicate that the SCL/TAL1 transcription factor which is activated in 25% of T-cell acute lymphoblastic leukemia (T-ALL), preserves long term HSC self-renewal activity by maintaining these cells in a quiescent state. SCL occupies a large number of loci in hematopoietic cells, among which Kit is well documented to sustain long term HSC self-renewal, survival and quiescence in adult mice, and to retain HSCs in their niches via interaction with membrane-linked Kit ligand. We now show that Scl and Kit are centrally involved in a feed forward loop that controls hematopoietic cell fate. In acute leukemias, the self-renewal capacity of leukemia initiating cells can be conferred by the cell of origin of leukemia, i.e. primitive HSCs. Alternatively oncogenes acting on committed progenitors can induce stemness genes, transforming non-self-renewing progenitors into pre-leukemic stem cells (pre-LSCs). We capitalized on a transgenic mouse model of T-ALL induced by thymic expression of two oncogenic transcription factors, SCL and LMO1 to show that SCL-LMO1 reprogram a subset of non-self-renewing double-negative thymocytes into self-renewing pre-LSCs. Surprisingly, the NOTCH1 oncogene which is activated in more than 55% of T-ALLs does not reprogram thymocytes on its own. Rather, NOTCH1 enhances the oncogenic reprogramming activity of SCL-LMO1 in a dosage-dependent manner. We will discuss how chromosomal translocations result in the inappropriate activation of HSC self-renewal genes in immature thymocytes and how oncogenic reprogramming differs from cellular reprogramming. Normal hematopoietic stem cells (HSCs) are uniquely endowed with long term self-renewal capacities to sustain blood cell production throughout life whereas progenitors and mature blood cells have finite life spans. HSCs normally reside in the protective microenvironment of the bone marrow where they remain dormant. These cells divide infrequently to produce mature hematopoietic cells without compromising the pool of HSCs. Our results indicate that the SCL/TAL1 transcription factor which is activated in 25% of T-cell acute lymphoblastic leukemia (T-ALL), preserves long term HSC self-renewal activity by maintaining these cells in a quiescent state. SCL occupies a large number of loci in hematopoietic cells, among which Kit is well documented to sustain long term HSC self-renewal, survival and quiescence in adult mice, and to retain HSCs in their niches via interaction with membrane-linked Kit ligand. We now show that Scl and Kit are centrally involved in a feed forward loop that controls hematopoietic cell fate. In acute leukemias, the self-renewal capacity of leukemia initiating cells can be conferred by the cell of origin of leukemia, i.e. primitive HSCs. Alternatively oncogenes acting on committed progenitors can induce stemness genes, transforming non-self-renewing progenitors into pre-leukemic stem cells (pre-LSCs). We capitalized on a transgenic mouse model of T-ALL induced by thymic expression of two oncogenic transcription factors, SCL and LMO1 to show that SCL-LMO1 reprogram a subset of non-self-renewing double-negative thymocytes into self-renewing pre-LSCs. Surprisingly, the NOTCH1 oncogene which is activated in more than 55% of T-ALLs does not reprogram thymocytes on its own. Rather, NOTCH1 enhances the oncogenic reprogramming activity of SCL-LMO1 in a dosage-dependent manner. We will discuss how chromosomal translocations result in the inappropriate activation of HSC self-renewal genes in immature thymocytes and how oncogenic reprogramming differs from cellular reprogramming.