Transcriptional reprogramming in neonatal hematopoietic stem and progenitor cells
July 21, 2021
Summary: This paper reviews the changes that blood forming stem and progenitor cells undergo as they transition from fetal to adult stages of life. The figure shows genes converting from “off” to “on” states in a stochastic manner to allow for gradual changes in overall gene expression.
Li Y, Magee JA. Transcriptional reprogramming in neonatal hematopoietic stem and progenitor cells. Exp Hematol. 2021 Sep;101-102:25-33. doi: 10.1016/j.exphem.2021.07.004. Epub 2021 Jul 23. PMID: 34303776; PMCID: PMC8557639.
Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy
February 16, 2021
Summary: This paper shows how a gene called KMT2C (or sometimes MLL3) controls hematopoietic stem cell fate. Kmt2c gets deleted cancers called myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Often, these deletions happen after patients have received chemotherapy for a different cancer. We showed that MLL3 deletions allow stem cells to regenerate themselves more extensively after chemotherapy than they should. This can lead to MDS or AML.
Chen R, Okeyo-Owuor T, Patel RM, Casey EB, Cluster AS, Yang W, Magee JA. Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy. Cell Rep. 2021 Feb 16;34(7):108751. doi: 10.1016/j.celrep.2021.108751. PMID: 33596429; PMCID: PMC7951951.
Single-cell analysis of neonatal HSC ontogeny reveals gradual and uncoordinated transcriptional reprogramming that begins before birth
August 20, 2020
Summary: This paper describes switches that guide neonatal hematopoietic stem cell (HSC) development, HSC fate and leukemia initiation. It provides a comprehensive characterization of the transcriptional changes that govern neonatal hematopoiesis. It identified type I interferon signaling as a late gestational switch that initiates perinatal progenitor expansion and sensitizes progenitors to FLT3-ITD.
Li Y, Kong W, Yang W, Patel RM, Casey EB, Okeyo-Owuor T, White JM, Porter SN, Morris SA, Magee JA. Single-cell analysis of neonatal HSC ontogeny reveals gradual and uncoordinated transcriptional reprogramming that begins before birth. Cell Stem Cell. 2020. doi:10.1016/j.stem.2020.08.001 PMID:32822583
The efficiency of murine MLL-ENL driven leukemia initiation changes with age and peaks during neonatal development
August 12, 2019
Summary: This paper shows that MLL-ENL, an AML driver mutation, initiates AML more efficiently in fetal/neonatal progenitors than in adult progenitors. This explains why the MLL-ENL is more common in infant AML than adult AML. It identifies Lin28b as a switch that modulates MLL-ENL transformation.
Okeyo-Owuor T, Patel RM, Li Y, Yang W, Casey EB, Cluster AS, Porter SN, Bryder D, Magee JA. The efficiency of murine MLL-ENL driven leukemia initiation changes with age and peaks during neonatal development. Blood Advances. 2019;3(15):2388-2399. DOI: 10.1182/bloodadvances.2019000554 PMCID:PMC6693010 PMID:31405949
Fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant to Flt3-ITD mutations
November 23, 2016
Summary: This paper shows that fetal blood progenitors resist transformation by the FLT3-ITD mutation, despite active FLT3 signaling. This provides an underlying mechanism for why AML mutations skew towards specific patient age groups (e.g. why FLT3-ITD mutations are rare in infant leukemia).
Porter SN, Cluster AS, Yang W, Busken KA, Patel RM, Ryoo JA, Magee JA. Fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant to Flt3-ITD mutations. eLife. 2016;5. DOI: 10.7554/eLife.18882 PMID:27879203