Although the present treatment options for patients with myelofibrosis (MF) clearly improve their performance status as well as symptoms related to splenomegaly, these approaches has not substantially altered the risk of disease progression or evolution to acute myeloid leukemia. MF arises ultimately at the level of the hematopoietic stem cell (HSC) due to a sequence of genetic events. These malignant MF HSCs and their progeny termed, hematopoietic progenitor cells (HPCs), reside not only within the marrow but also within extra medullary sites such as the spleen. The components of these tissue specific microenvironments act in close proximity to create niches which favor the predominance of malignant HSC/HPC at the expense of normal HSC/HPC. This interplay between the intrinsic properties of MF HSC/HPC and these tissue specific micro- environments results in an inflammatory milieu which promotes MF disease progression. We hypothesize that improvement in the outcomes of MF patients can only be achieved by the implementation of strategies which result in the depletion or actual elimination of MF HSCs and re-establishment of normal hematopoiesis. To accomplish this goal, we hypothesize that the administration of a combination of drugs will be required which would be capable of depleting malignant HSCs as well as disarming the MF HSC promoting microenvironment. Recently, we have demonstrated that MF HSCs are characterized by up-regulation of HDM2 which promotes the proteosomal degradation of p53. Treatment with nutlins, which antagonize the activity of HDM2, up- regulates p53 resulting in the selective depletion of MF HSCs. We recognize that the MF inflammatory milieu is the consequence of up-regulation of NF-?B, a transcription factor which controls pro-inflammatory cytokine production by both myeloid and microenvironmental cells. Increments in p53 levels are also capable of antagonizing NF-?B thereby providing a pharmacological tool with which to blunt the MF inflammatory milieu. We will, therefore, plan to deplete or eliminate MF HSCs by not only up-regulating p53 within MF HSCs, but also within myeloid and microenvironmental cells. Treatment of MF myeloid cells with a nutlin led to the reduction of the production of a number of cytokines including lipocalin-2 which promotes the predominance of MF HSCs over normal HSCs and acts to create an MF like microenvironment. Furthermore we will also target the MF HSC microenvironment by utilizing a CXCR1/CXCR2 (IL-8 receptor) antagonist thereby eliminating actions of IL-8, a chemokine produced in response to lipocalin2 by splenic microenvironmental cells, which promotes the development of MF-HSC promoting vascular niches within the spleen. In addition, we will utilize bromodomain inhibitors to down regulate NF-?B in order to further reduce the elaboration of MF promoting cytokines including IL-8. The combinations of drugs identified by the completion of these planned studies will enact the two pronged strategy outlined above to deplete MF HSCs and will be subsequently evaluated in several paradigm shifting phase1/2 clinical trials in MF patients (Project 4).

Public Health Relevance

Although efforts to target tumor stem cells and the tumor microenvironment for a variety of tumor types have been ongoing for almost 2 decades, progress in this area has been frustratingly slow. If this approach is valid, it will most likely be successfully tested in a disease such as myelofibrosis where the stem origin and tumor promoting micro environmental influences are irrefutable and where the involved tissues are easily accessible. To test this hypothesis, combinations of drugs will be identified which are capable of depleting myelofibrosis HSCs as well as disarming myelofibrosis HSC supportive microenvironments which will subsequently be evaluated in clinical trials.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Icahn School of Medicine at Mount Sinai
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Migliaccio, Anna Rita; Varricchio, Lilian (2018) Concise Review: Advanced Cell Culture Models for Diamond Blackfan Anemia and Other Erythroid Disorders. Stem Cells 36:172-179
Ling, Te; Crispino, John D; Zingariello, Maria et al. (2018) GATA1 insufficiencies in primary myelofibrosis and other hematopoietic disorders: consequences for therapy. Expert Rev Hematol 11:169-184
Migliaccio, Anna Rita; Uversky, Vladimir N (2018) Dissecting physical structure of calreticulin, an intrinsically disordered Ca2+-buffering chaperone from endoplasmic reticulum. J Biomol Struct Dyn 36:1617-1636
Peeken, Jan C; Jutzi, Jonas S; Wehrle, Julius et al. (2018) Epigenetic regulation of NFE2 overexpression in myeloproliferative neoplasms. Blood 131:2065-2073
Wang, Xiaoli; Hu, Cing Siang; Petersen, Bruce et al. (2018) Imetelstat, a telomerase inhibitor, is capable of depleting myelofibrosis stem and progenitor cells. Blood Adv 2:2378-2388
Zimran, Eran; Tripodi, Joseph; Rampal, Raajit et al. (2018) Genomic characterization of spleens in patients with myelofibrosis. Haematologica 103:e446-e449
Kleppe, Maria; Koche, Richard; Zou, Lihua et al. (2018) Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms. Cancer Cell 33:785-787
Qiu, Jiajing; Salama, Mohamed E; Hu, Cing Siang et al. (2018) The characteristics of vessel lining cells in normal spleens and their role in the pathobiology of myelofibrosis. Blood Adv 2:1130-1145
Pronier, Elodie; Cifani, Paolo; Merlinsky, Tiffany R et al. (2018) Targeting the CALR interactome in myeloproliferative neoplasms. JCI Insight 3:
Migliaccio, Anna Rita (2018) A vicious interplay between genetic and environmental insults in the etiology of blood cancers. Exp Hematol 59:9-13

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