Juvenile myelomonocytic leukemia (JMML) is the most common myeloproliferative neoplasm (MPN) in childhood, and tends to occur in very young children less than 4 years of age. JMML is traditionally characterized as being Ras-driven due to mutations in NF1, CBL, KRAS, NRAS, or PTPN11. Traditional cytotoxic chemotherapeutic agents are ineffective in JMML, and the only curative modality is allogeneic hematopoietic stem cell transplantation. Unlike other MPNs, JMML rarely progresses to blast crisis; rather, mortality is due to extramedullary tumor cell expansion leading to organ failure, respiratory failure, bleeding, or infection. Notably, following allogeneic stem cell transplant, 50% of children succumb to leukemia relapse. This relapse rate in JMML is substantially higher than that of individuals who receive allogeneic stem cell transplant for chronic myelogenous leukemia (CML) in chronic phase (approximately 7% leukemia relapse), implicating a strong hematopoietic stem cell (HSC)-independent component of JMML development and progression. We envision two distinct mechanisms that potentially account for a HSC-independent means of JMML relapse after allogeneic HSC transplant. First, the JMML-initiating malignant cells may emerge during embryonic development prior to and independently from HSCs, and persist postnatally as self-replenishing malignant tissue macrophages. Alternatively, regardless of the origin of the JMML cells, the hyperinflammatory nature of JMML may damage the bone marrow microenvironment, prohibiting the expansion of normal donor cells following transplant, permitting residual leukemia cells to outcompete the normal graft, and leading to leukemia relapse. To address these possibilities, we will use the tamoxifen-inducible Cre recombinase system, which will permit yolk sac-restricted expression of the common JMML mutation, Shp2D61Y, to determine if yolk sac-restricted oncogene expression is sufficient for the post-natal development of MPN. Further, we will examine if inhibition of the pro-inflammatory protein, PI3K p110?, improves homing, engraftment, expansion, and myeloid differentiation of WT donor cells into diseased, Shp2D61Y-expressing recipients.

Public Health Relevance

Juvenile myelomonocytic leukemia (JMML) is a fatal childhood disease that is not amenable to standard chemotherapeutic regimens and demonstrates a very high leukemia relapse rate following allogeneic hematopoietic stem cell transplantation. We have outlined a series of studies that interrogate hematopoietic stem cell-independent mechanisms that potentially account for this high relapse rate, including chemotherapy- resistant tissue resident macrophages or an altered, hostile bone marrow microenvironment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA202296-01A1
Application #
9178088
Study Section
Special Emphasis Panel (ZCA1-SRB-C (M2))
Program Officer
Mufson, R Allan
Project Start
2016-07-01
Project End
2018-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$169,650
Indirect Cost
$60,900
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Deng, Lisa; Richine, Briana M; Virts, Elizabeth L et al. (2018) Rapid development of myeloproliferative neoplasm in mice with Ptpn11 D61Y mutation and haploinsufficient for Dnmt3a. Oncotarget 9:6055-6061
Tarnawsky, Stefan P; Yu, Wen-Mei; Qu, Cheng-Kui et al. (2018) Hematopoietic-restricted Ptpn11E76K reveals indolent MPN progression in mice. Oncotarget 9:21831-21843
Deng, Lisa; Virts, Elizabeth L; Kapur, Reuben et al. (2017) Pharmacologic inhibition of PI3K p110? in mutant Shp2E76K-expressing mice. Oncotarget 8:84776-84781
Tarnawsky, Stefan P; Kobayashi, Michihiro; Chan, Rebecca J et al. (2017) Mice expressing KrasG12D in hematopoietic multipotent progenitor cells develop neonatal myeloid leukemia. J Clin Invest 127:3652-3656
Tarnawsky, Stefan P; Yoshimoto, Momoko; Deng, Lisa et al. (2017) Yolk sac erythromyeloid progenitors expressing gain of function PTPN11 have functional features of JMML but are not sufficient to cause disease in mice. Dev Dyn 246:1001-1014