Leukemogenic Kras mutation reprograms multipotent progenitors to facilitate its spread through the hematopoietic system

We studied how leukemia-associated mutations subvert normal adult hematopoiesis by genetically inducing them in specifically in murine hematopoietic stem cells (HSC) followed by lineage tracing in native hosts. Leukemia-initiating mutations such as Tet2 or Dnmt3a deletions did not increase the net HSC contribution in the steady state, whereasTet2 deletion slightly accelerated HSC contribution to myeloid lineages following microbial stimulation. In contrast, the leukemia-transforming KrasG12D mutation dramatically accelerated the contribution of mutant HSC to all hematopoietic lineages, rapidly creating a pre-leukemic state. The acceleration was mediated by KrasG12D-carrying multipotent progenitors (MPP) that rapidly outcompeted normal MPP and showed increased proliferation but lacked self-renewal capacity. In addition, mutant progenitor cells expressed the secreted stem/progenitor regulator osteopontin and showed enhanced CXCR4-dependent motility, both of which contributed to the accelerated spread of the mutation to mature cells. Thus, transforming mutations may facilitate their spread from HSC to mature cells via hypercompetitive progenitors, creating a two-component stem/progenitor circuit that underlies leukemogenesis. Overall design: Pdzk1ip1-CreER R26Tom or Pdzk1ip1-CreER R26Tom KrasG12D mice were treated with 0.5mg of tamoxifen. After 3 weeks post-induction, bone marrow cells were stained with hashtags FACS antibodies. For KrasG12D group, Tom+ Lin- Sca-1+ c-Kit+ (LSK) cells were sorted and for WT group, total LSK cells were sorted.