Research

The Deininger Lab has a long-standing interest in the biology and therapy of leukemia, specifically chronic myeloproliferative neoplasms (CMPN), including chronic myeloid leukemia (CML) and Philadelphia chromosome (Ph)-negative CMPN. CML and Ph-negative CMPN are hematopoietic cancers that are thought to arise from the transformation of a hematopoietic stem or progenitor cell.

Unifying features of CMPN include the expansion of one or more of the myeloid lineages, an initial chronic phase with retained terminal differentiation capacity and an increased risk of progression to acute leukemia. Constitutive activation of tyrosine kinases is common in CMPN. A well-known example is CML, which is caused by BCR-ABL, a fusion kinase derived from t(9;22)(q34;q11), which is cytogenetically visible as the Philadelphia chromosome (Ph). Another example is the JAK2V617F allele, which is present in almost all patients with polycythemia vera and some 50% of patients with primary myelofibrosis and essential thrombocythemia. Other CMPN patients harbor mutations that deregulate the RAS pathway or growth factor signaling.

Imatinib (Gleevec), a small molecule tyrosine kinase inhibitor (TKI) of BCR-ABL, has revolutionized the therapy of CML and for most patients treated in chronic phase has transformed a lethal disease into a chronic condition that is treatable with few side effects. Unfortunately, the results of TKI therapy are much more modest in patients who have progressed to blast crisis, where responses are only transient. Many of these patients have acquired point mutations in the tyrosine kinase domain of BCR-ABL that impair imatinib binding.

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However, in a considerable proportion of patients, resistance remains mechanistically unexplained and is an area of active study. An even more common problem than resistance is the fact that imatinib therapy must be continued even in patients with stable and profound responses, as leukemic stem cells persist and lead to recurrence of active disease upon discontinuation of drug. Other types of leukemia with activated tyrosine kinase alleles, such as acute myeloid leukemia with FLT3 mutations, and JAK2V617F-positive CMPN, have proven less amenable to TKI therapy, probably reflecting more complicated disease biology. Thus, neither is the CML story complete nor have we been able to translate the success of imatinib to leukemias other than CML.

Research in the Deininger Lab is funded by the Leukemia & Lymphoma Society and the National Institutes of Health (NCI and NHLBI). We currently focus on three main areas:

  1. The mechanisms underlying resistance of CML cells to tyrosine kinase inhibitors. Although mutations in the kinase domain are a major mechanism of resistance, many patients with clinical resistance do not have such mutations, and other causes must be involved. We use a variety of technologies including phosphotyrosine FACS and gene expression arrays on primary leukemia cells to discover alternative resistance mechanisms, with a view on exploiting them therapeutically.
  2. The biology of disease persistence in CML patients treated with imatinib. Using human cells and murine models, we investigate which mechanisms allow CML cells to survive despite continued therapy with tyrosine kinase inhibitors. We are particularly interested in the potential role the microenvironment may play in this process.
  3. Novel therapeutic targets in CMPN. We use a variety of assays, including genome-wide scanning tools, to discover novel therapeutic targets in patients with CMPN other than CML, for example chronic myelomonocytic leukemia (CMML). We will use the knowledge to develop biomarkers for risk stratification and to design novel rational therapies.

The philosophy of our lab is translational—we work along clinical questions, but are not shy of looking into mechanisms if this is where our research takes us. We believe that we can learn in the laboratory what to do next in the clinic and learn in the clinic what to do next in the lab.

Principle Investigator

Michael W. Deininger, MD, PhD
Senior Director of Transdisciplinary Research, Principal Investigator
Email

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