Ravindra Majeti
Stanford University, CA·Genetics
Acute myeloid leukemia (AML) is an aggressive cancer of the bone marrow that affects more than 20,000 American adults a year; even with intensive chemotherapy or a bone marrow transplant, only 30-40% survive five years. Research has shown that AML does not arise in one step.
- Fields
Genetics
Medicine & Clinical Research
Biology
- Topics
acute myeloid leukemia
hematopoietic stem cells
pre-leukemic stem cells
- Grants
- 2 known grants, through Dec 2029
What they work on
- Determine how long the pre-leukemic phase lasts in people who progress to acute myeloid leukemia, and whether that duration affects how the disease develops.
- Identify what distinguishes the pre-leukemic hematopoietic stem cell clone that eventually transforms into AML from the other blood cell types the same clone produces.
- Test whether the size of the pre-leukemic clone shapes the resulting leukemia, and whether that influence is direct or acts through effects on neighboring cells.
- Correct specific mutations in primary patient AML cells and AML-derived iPSCs using CRISPR/Cas9 with rAAV6 homology directed repair, and measure effects on leukemia stem cell frequency, disease initiation and maintenance.
- Track the number and dynamics of individual leukemia stem cells in vivo using CRISPR-inserted DNA barcodes and mitochondrial single-cell ATAC-seq in patient samples, xenografted mice and during therapy.
- Test the leukemia stem cell model by engineering inducible caspase 9, a suicide switch, into a leukemia-stem-cell-specific gene and activating it in vivo to see whether removing these cells eradicates the leukemia.
More about the research
Mutations accumulate one after another in blood-forming (hematopoietic) stem cells, the self-renewing cells that make all blood. Cells carrying only some of those mutations are called pre-leukemic stem cells, and once leukemia is established a small self-renewing subset, leukemia stem cells, is thought to sustain it. Two projects address the two ends of this story: what happens during the long pre-leukemic phase, and what leukemia stem cells actually do once the disease exists.
Why it matters
Survival in acute myeloid leukemia remains poor, and relapse is common because the cells that regenerate the disease may survive treatment. Pinpointing which mutations leukemia stem cells need, how many such cells there are, and whether removing them alone eliminates the leukemia would show whether stem-cell-directed therapy is worth pursuing. Understanding the long pre-leukemic phase and clonal hematopoiesis could also inform who is at risk and when intervention might prevent AML.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Xunlei Kang
University of Missouri-Columbia, MO·Medicine & Clinical Research
Determine how DPP4, a cell-surface enzyme, controls the location, survival and self-renewal of human AML stem cells, using colony-forming assays and mice carrying human AML cells.
Britta Will
Albert Einstein College of Medicine, NY·Biology
Map when chaperone-mediated autophagy (CMA), a selective protein-recycling pathway, is active in precancerous CHIP blood stem cells and leukemic stem cells, using a CMA reporter mouse and lentiviral CMA biosensors in patient cells.
Wei Du
University of Pittsburgh, PA·Medicine & Clinical Research
Examine how TREM1, a stress-induced immune receptor, acts within leukemia-associated macrophages during leukemia development, using inducible macrophage-specific Trem1 knockout mice in Fanca-deficient and MLL-AF9 leukemia models.
The school
Stanford University: 87 labs on PI Pages, $1.6B a year on research, 739 research doctorates a year.
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