The Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders, which include Polycythemia Vera (PV), Essential Thrombocytosis (ET), and Primary Myelofibrosis (PMF)). MPNs carry a risk of morbidity and mortality. Importantly, however, a substantial proportion of patients with PV, ET or PMF develop transformation to acute myeloid leukemia (AML). This progression is often fatal, with a median survival of less than four months. Standard treatments available for AML have proven to have little or no impact on outcome in these patients. Thus, there is a pressing need to develop new treatments. Using target gene analysis, we have begun genomic assessment of post- MPN AML. Our preliminary data demonstrates that the mutations found at the time of leukemic transformation (LT) differs from those commonly found in de novo AML. This data suggests that post-MPN AML is genetically distinct from de novo AML, and that more expansive efforts are required to further define the spectrum of mutations in post-MPN AML. We have developed the first reported genetically accurate murine model of post-MPN AML. We have performed detailed analysis of this initial model. Further, using this model, we have begun testing new therapeutic strategies in vivo and in vitro. We seek to further understand the genetic events that are involved in the progression of MPN to AML. This information will then be used to develop new genetically accurate pre-clinical models of progression to AML. We then plan to use these models to test new therapeutic strategies. Using the genetic and biological insights we will gain from these efforts, we seek to ultimately translate these findings into new therapeutic strategies for this devastating disease. The studies will be led by Dr. Raajit Rampal, a junior faculty member at Memorial Sloan-Kettering Cancer Center under the mentorship of Dr. Ross Levine. Dr. Levine is a leader in leukemia research with an established track record of effectively, rapidly mentoring former trainees into independence. The Memorial Sloan-Kettering Cancer Center, and the Human Oncology and Pathogenesis program, led by Dr. Charles Sawyers, offers an exceptional environment for cultivating a developing career in translational cancer research. To achieve his long-term goal of becoming an independent investigator Dr. Rampal has developed a structured curriculum of activities aimed at broadening her knowledge base, expanding technical repertoire and developing leadership skills, and has assembled an advisory committee of leading scientists.

Public Health Relevance

The Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) are a group of clonal hematopoietic stem cell disorders, which include Polycythemia Vera (PV), Essential Thrombocytosis (ET), and Primary Myelofibrosis (PMF). A substantial proportion of patients with PV, ET or PMF develop transformation to acute myeloid leukemia (AML), which in most cases do not respond to current therapies. We seek to determine the genetic and functional basis for transformation from MPNs to AML, and ultimately target these elucidated pathways for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08CA188529-01
Application #
8747728
Study Section
Subcommittee G - Education (NCI)
Program Officer
Perkins, Susan N
Project Start
2014-09-10
Project End
2019-08-31
Budget Start
2014-09-10
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$178,200
Indirect Cost
$13,200
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Zimran, Eran; Tripodi, Joseph; Rampal, Raajit et al. (2018) Genomic characterization of spleens in patients with myelofibrosis. Haematologica 103:e446-e449
Tremblay, Douglas; Sokol, Kelsey; Bhalla, Sheena et al. (2018) Implications of Mutation Profiling in Myeloid Malignancies-PART 1: Myelodysplastic Syndromes and Acute Myeloid Leukemia. Oncology (Williston Park) 32:e38-e44
Sokol, Kelsey; Tremblay, Douglas; Bhalla, Sheena et al. (2018) Implications of Mutation Profiling in Myeloid Malignancies-PART 2: Myeloproliferative Neoplasms and Other Myeloid Malignancies. Oncology (Williston Park) 32:e45-e51
Xiao, Wenbin; Rampal, Raajit; Zhang, Yanming et al. (2018) JAK/MAP kinase pathway activation and TP53 mutations in acute leukemia with megakaryocytic and erythroid differentiation. Leukemia 32:1842-1845
Papo, Matthias; Diamond, Eli L; Cohen-Aubart, Fleur et al. (2017) High prevalence of myeloid neoplasms in adults with non-Langerhans cell histiocytosis. Blood 130:1007-1013
Crawford, Jeffrey; Becker, Pamela Sue; Armitage, James O et al. (2017) Myeloid Growth Factors, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 15:1520-1541
Durham, Benjamin H; Roos-Weil, Damien; Baillou, Claude et al. (2017) Functional evidence for derivation of systemic histiocytic neoplasms from hematopoietic stem/progenitor cells. Blood 130:176-180
Kotini, Andriana G; Chang, Chan-Jung; Chow, Arthur et al. (2017) Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to Transplantable Leukemia. Cell Stem Cell 20:315-328.e7
Chellapandian, Deepak; Makras, Polyzois; Kaltsas, Gregory et al. (2016) Bisphosphonates in Langerhans Cell Histiocytosis: An International Retrospective Case Series. Mediterr J Hematol Infect Dis 8:e2016033
Rampal, Raajit; Figueroa, Maria E (2016) Wilms tumor 1 mutations in the pathogenesis of acute myeloid leukemia. Haematologica 101:672-9

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