JMML Research Roadmap
New!!!  As of 12/05/2015


Go to "About the JMML Research Roadmap"


 Roads to a Cure  Potential methods of addressing each question
 Pathophysiology  
 1. Is JMML caused by RAS pathway mutations alone or are second hits required? What is the risk stratification?  Can we identify driver mutations in patients lacking RAS pathway mutations?   Analysis of JMML specimens, especially in patients after relapse (e.g. SNP-A, Genomic Sequencing)
 2. What are the molecular mechanisms in patients with RAS pathway mutations that lead to myeloproliferation in patients with JMML? How do newly-identified secondary mutations and non-coding RNA affect JMML?   Murine models, biochemical analyzes, functional studies to determine what parts of the pathway compensate for each other; Evaluation of mutations in hematopoietic cell sub-populations; Utilize CRISPR to add new mutations to existing mutations.
 3. Identify the difference between JMML and JMML-like disease (e.g. RALD).  TBD
 4. Is the outcome of JMML influenced by inherited variance?  Large international database.
 Murine models  
  1. Are current mouse models of JMML (e.g. conditional K-RasG12D, PNAS 2004:101:597-602, Shp2 gain of function, Loss of NF1) suitable to test new agents before these drugs are tested in clinical trials?  Complex experiments in murine models that need verification in clinical trials
  2. Do we have a xenograft model that is complementary to the genetic models? – completed, a neonatal xenograft model now exists as of Dec 2015  Development of a xenograft murine model
 3. How do secondary mutations affect the RAS pathway mutations in promoting JMML?  Cross RAS pathway mutant mice with mice bearing secondary mutations
 From bench to bedside  
 1. How can we effectively inhibit disruptive signaling networks, inclusive of RAS?   Collaboration with structural biologists, Biochemistry – e.g. Trimatenib trial
 2. Does targeted therapy of disruptive signaling networks, inclusive of RAS, lead to a durable clinical response?  Biochemistry, cell culture, murine models, clinical trials
 3. Have we tested a promising drug and then put it into the clinic quickly, thereby avoiding expensive and time-consuming testing of drugs that are promising but will not be able to be put into the clinic?

 Complex experiments in multiple murine models – e.g. Azacytadine trial

 4. Have we conducted robust pre-clinical testing of MEK or PI3K inhibitors in murine models before attempting to move these drugs into trials?completed; some inhibitors work and this data has been published, but they are not yet in clinical trials

 Complex experiments in multiple murine models; List of promising drugs at each stage of clinical trials; JMML Foundation intervention to request access to promising agents

 5. Is there a therapeutic window due to the toxicity of targeted therapies?  International clinical trials
 6. Will inhibitors of the RAS pathway need to be combined with hematopoietic stem cell transplantation?  International clinical trials
 7. Have we conducted an international phase 2 drug trial?

 International phase 2 drug trial; potential Azacytadine trial with institutions in Europe and NA

 8. Would t-cell targeted immunotherapy be effective in JMML? Dendritic cell vaccines?   Use an anti-AML CAR for treatment of JMML in a pre-clinical trials
 Clinical management  
 1. Do patients with RAS mutations require the same treatment as patients with PTPN11 mutations or patients with NF1, or are there clinical differences?  Meta-analysis of international patient data; future clinical trials that incorporate internationally standardized laboratory assays at diagnosis and follow-up
 2. Are there differences in prognosis within the known mutational groups?  Meta-analysis of international patient data; future clinical trials that incorporate internationally standardized laboratory assays at diagnosis and follow-up

 3. How can we predict a stable clinical course without specific treatment (consider focus on KRAS and NRAS mutant patients)?

 Meta-analysis, murine models and careful characterization of individual patients; monocyte subsets; minimally targeted sequencing of myeloid panel; auto-antibody panel

 4. What is the best transplant regimen for patients with JMML?  International clinical trials
 5. How do we optimize immunosuppression to allow for graft versus leukemia effects and to prevent graft versus host disease?  International clinical trials

 6. Can we agree on uniform diagnostic response and relapse criteria? – yes, this data has been published!

 International Symposia/Working Group Meetings

 7. What is the best method of minimal residual disease assessment?

 International clinical trials; convert research into using digital PCR into a CLIA-approved test

 8. Is there any role for pre-SCT chemotherapy or kinase inhibitor therapy?

 Complex experiments in murine models; international clinical trials; Trimatenib and Azacytadine trials; international database

 9. Is there any role for post-SCT chemotherapy or kinase inhibitor therapy?  Complex experiments in murine models; international clinical trials

 10. What is the natural history of germline mutations and what is the propensity to develop JMML and other diseases? (CBL) - removed from Roadmap due to feeling that this question is not as urgent as others in terms of progressing towards a cure

 A Ras pathway clinic at NIH


About the JMML Research Roadmap

The JMML Research Roadmap is a vehicle through which affected families, new researchers, and donors alike can visualize the way forward for JMML research. It shows some of the most important current questions about JMML. Answering these questions now will help doctors better understand how JMML works and improve their care for patients.

The JMML Foundation Medical Advisory Committee, chaired by Dr. Christian Kratz of the University of Freiburg, Germany, divided the many possible roads to a cure into four categories: Pathophysiology, From bench to bedside, Murine models, and Clinical management.

Eighteen critical questions were identified as starting points for future research, and potential strategies for addressing each question related to JMML are presented (see table on next page). As noted by Professor Henrik Hasle of the Aarhus University Hospital, Denmark, “it is very appropriate and useful for putting the different scientific questions into perspective.”

Researchers cannot focus solely on the questions in the Roadmap, however, since their research may lead them into unforeseen directions that deserve follow up. Likewise, individual researchers may choose different strategies to answer these questions according to their areas of expertise and their institutions’ resources. This model, therefore, simply estimates the work that lies ahead on the path to a cure for JMML and is designed for ease of update as new questions, and answers, emerge.

What’s next? The JMML Foundation is using this JMML Research Roadmap now to create a research grant process. Through this process, donated funds will be directed to high pay-off targets on the road to a cure. Estimating the cost to answer any particular research question is impossible, though, as it may take many approaches to find the one that works. For an idea of how much it costs to execute a research project, consider how other nonprofits fund leukemia research:
  • Leukemia Lymphoma Society (LLS) Career Development Grants: $55,000, $65,000, or $110,000 per year for 3 to 5 years
  • Leukemia Research Foundation New Investigator Grants: Up to $100,000 per year
  • LLS Translational Research Grants: Up to $200,000 over 3 years
  • LLS Specialized Center of Research Grants: Up to $6,250,000 over 5 years
Clearer direction for JMML research. Less uncertainty and greater confidence in the research process. A rallying point for research funding. Increased international coordination. Faster progress to a cure. These are some of our aims, supported by the JMML Research Roadmap. We welcome your thoughts and urge your support to make these goals a reality.


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