The Effects Of Leukemic Environment On Hematopoietic Stem/Progenitor Cells In The Mice Bearing Notch1-induced Leukemia

In this study, we have established the intracellular domain of Notch1 (ICN1) over-expressing murine acute T lymphoblastic leukemia (T-ALL) model to quantitatively study the function of residual hematopoietic primitive cells in leukemic environment. Methods We took the approaches of quantitative clonal assay in vitro and competitive bone marrow transplantation (cBMT) to directly assess the possible impact of leukemic environment on self-renewal and long-term engraftment of HSC, with no leukemia but irradiated transplantation model as control group. Results 1.Enforced expression of ICN1 induces T-ALL with 100% penetration;2. Hematopoietic suppression at both stem and progenitor cell levels in the leukemia-bearing mice;3. Increased proliferation but not survival of the residual normal hematopoietic cells in the leukemic marrow; 4. Functional preservation of HSC in the leukemic marrow; 5. In leukemic environment, self-renewal related pathway was activated in the primitive hematopoietic compartment, and the alterations on transcription level of cell cycle regulation genes keep HSC in a more stable status. Conclusions Our current study demonstrates for the first time that pan-scale repression of hematopoietic cells in leukemic environment was directly related to decreased pool sizes and phenotype frequencies of hematopoietic primitive cells. It is the first report demonstrating that HSC can be directly suppressed in the leukemic environment. To our surprise, the HSC isolated from the leukemic hosts even function better in the secondary recipients as compared to the cells from the non-leukemic but irradiated hosts. Therefore, our data suggest that although the hematopoietic suppression was occurred at both stem and progenitor cell levels in the leukemia-bearing mice, the normal stem cell candidates were kept in the dormant status with reservation of self-renewal potential.