Awardee OrganizationBOSTON UNIVERSITY MEDICAL CAMPUS
Description
Abstract Text
PROJECT SUMMARY/ABSTRACT
The major shortcoming of current cancer therapies is the inability to target the leukemic stem cells, despite initial
success in eliminating the bulk of leukemic cells. Primary myelofibrosis (PMF) belongs to the group of
myeloproliferative neoplasms (MPNs), the fourth most prevalent hematological malignancy. In the United States,
~100,000 people are living with or in remission from MPNs. The most frequent driver mutation is JAK2V617F. JAK2
inhibitor ruxolitinib remarkably alleviates constitutive symptoms, but does not prolong survival or reverse disease,
which progresses to myelofibrosis or transforms to acute myeloid leukemia. Mouse models and patient data
suggest that this shortcoming is due to its inability to target the JAK2V617F+ stem cell. This application addresses
the urgent need to develop treatments that specifically target JAK2V617F+ stem cells to improve the long-term
outcome of current therapies. Previous work on the SERCA K01 award revealed de-regulated expression of
integrins, adhesion molecules that integrate the extracellular environment with the actin cytoskeleton, in
megakaryocytes of JAK2V617F transgenic mice and PMF patients. The central hypothesis of this proposal is that
1 integrin is a key mediator of JAK2V617F+ stem cell maintenance in PMF. In our most recent preliminary studies,
we found higher activation of 1 integrin in stem cells of JAK2V617F transgenic mice compared to wild-type (WT)
controls. Treatment with an anti-1 integrin inhibitory antibody HM1-1 in vivo was able to dramatically reduce
the number of JAK2V617F+ stem cells, with negligible effect on WT animals. However, it is critical to understand
what makes the JAK2V617F+ stem cells particularly susceptible to 1 integrin inhibition, and whether the stem cell
reduction persists long-term. AIM 1 of this proposal, of mechanistic significance, will define how the anti-1
integrin antibody HM1-1 reduces JAK2V617F+ stem cells in vivo, by addressing two hypotheses: 1) that induction
of cell cycle leads JAK2V617F+ stem cells to exit quiescence and differentiate, and 2) that HM1-1 induces
apoptosis and cell death in JAK2V617F+ stem cells. AIM 2, of translational significance, will address the hypothesis
that JAK2V617F+ stem cell reduction upon HM1-1 treatment persists long-term, and will lead to reduction of all
progeny derived from JAK2V617F+ stem cells. Studies will be performed on JAK2V617F transgenic mice, carrying
the human mutation, using state-of-art flow cytometric analysis of hematopoietic stem cells. Importantly, despite
its essential role in organism development, conditional deletion of 1 integrin in hematopoietic cells of adult mice
did not affect blood cell production or maintenance of stem cells. In contrast, as our data suggest, JAK2V617F+
stem cells seem to be particularly dependent on integrin signaling and highly sensitive to its inhibition, offering a
possible therapeutic opportunity window. This proposal addresses the unmet need of identifying a molecular
target specific to JAK2V617F+ stem cells with potential for therapeutic development. The AIMS of the proposal will
provide important preliminary data which will serve as a basis for mechanistic studies to be proposed in an
ensuing R01 grant application in support of applicant’s independent research career.
Public Health Relevance Statement
PROJECT NARRATIVE
The proposed research is an innovative approach to an unmet need in the treatment of hematological
malignancies: the inability to target malignant stem cells, the source of relapse and disease progression. We
discovered a new druggable target molecule that can specifically reduce the number of malignant stem cells in
primary myelofibrosis caused by the JAK2V617F mutation. If successful, this application will address the urgent
need to develop treatments that specifically target JAK2V617F stem cells to produce better long-term outcomes
than current therapies.
No Sub Projects information available for 5R03OD031959-02
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