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Targeting Novel Pathways in JMML

Award Number: R01HL146137
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Targeting Novel Pathways in JMML - PROJECT SUMMARY/ABSTRACT Juvenile myelomonocytic leukemia (JMML) is a common myeloproliferative neoplasm (MPN) in childhood. JMML is characterized as being Ras-driven due to mutations in NF1, CBL, KRAS, NRAS, or PTPN11, and cells from JMML patients show hypersensitivity to GM-CSF. Chemotherapeutic agents are mostly ineffective in JMML, and the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT). A common clinical picture in JMML is that it presents as a hyperinflammatory syndrome, and is often difficult to distinguish from viral infections. Thus, a component of JMML is associated with hyperinflammatory state and hyperactive innate immune cells. Further, unlike other MPNs, JMML rarely progresses to blast crisis; rather, mortality is due to extramedullary myeloid cell expansion leading to organ failure. Importantly, following allogeneic HSCT, 50% of patients succumb to leukemia relapse, implicating a role for bone marrow microenvironment (BME) in JMML development and progression. The hyperinflammatory nature of JMML may damage the BME, altering the expansion of normal donor cells following transplant, permitting residual leukemia cells to outcompete the normal graft, and leading to relapse. Utilizing mouse models of JMML, we demonstrate relapse in mice bearing PTPN11 mutations, we show altered composition of the BME in PTPN11 bearing mice and provide evidence that JMML patients that have a higher neutrophil count at the time of HSCT are more likely to relapse. These data combined with previous studies demonstrating hyperactive and inflamed neutrophils due to PTPN11 mutations suggests that these cells may contribute to relapse. We will examine this in detail. We have been analyzing multiple RNA sequencing datasets for lncRNAs that are differentially expressed in JMML. In doing so, we identified several novel lncRNAs whose expression is differentially regulated. We will examine how one of these lncRNAs contributes to JMML pathogenesis. We have recently shown that PI3K catalytic subunit p110δ contributes to both Akt and Erk hyperactivation, and promotes PTPN11-induced GM-CSF hypersensitivity and hyperproliferation, thus partially contributing to the progression of JMML. Given the lack of complete rescue by loss of p110δ in PTPN11-induced JMML, we sought out putative tyrosine kinases that signal together with p110δ in the PI3K-Akt signaling pathway that must be targeted for optimal JMML therapy. We present preliminary data demonstrating that Bruton's Tyrosine Kinase (BTK) inhibition collaborates with PI3K p110δ inhibition to reduce the activation of Akt and Erk in PTPN11-expressing cells. We will study the mechanism behind this cooperation. Overall, the proposed Aims will shed novel insight into JMML development and pathogenesis as well as identification of novel therapeutic targets.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Blood Diseases and Resources Research	000	4	5/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $542,416 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Blood Diseases and Resources Research	001	4	6/8/2022	NON-COMPETING CONTINUATION	$54,242
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Blood Diseases and Resources Research	000	4	12/31/2021	NON-COMPETING CONTINUATION	$488,174
														Subtotal = $542,416

Issue Date FY: 2021 ( Subtotal = $542,416 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Blood Diseases and Resources Research	000	3	1/5/2021	NON-COMPETING CONTINUATION	$488,174
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Blood Diseases and Resources Research	001	3	5/19/2021	NON-COMPETING CONTINUATION	$54,242
														Subtotal = $542,416

Issue Date FY: 2020 ( Subtotal = $534,541 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Blood Diseases and Resources Research	001	2	3/13/2020	NON-COMPETING CONTINUATION	$26,726
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Blood Diseases and Resources Research	000	2	12/27/2019	NON-COMPETING CONTINUATION	$507,815
														Subtotal = $534,541

Issue Date FY: 2019 ( Subtotal = $534,541 )
2019	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Blood Diseases and Resources Research	000	1	1/11/2019	NEW	$534,541
														Subtotal = $534,541

Grand Total All Awards = $2,153,914

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Targeting Novel Pathways in JMML

Award Number: R01HL146137

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/15/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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