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Molecular and Cellular Mechanisms of Chronic Myelomonocytic Leukemia (CMML)

Award Number: R01CA152108
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/02/2011
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Molecular and Cellular Mechanisms of Chronic Myelomonocytic Leukemia (CMML) - PROJECT SUMMARY/ABSTRACT Chronic myelomonocytic leukemia (CMML) is a devastating cancer with an urgent and unmet need for effective therapies (median survival: ~28 months). Approximately 30% of CMML cases evolve to acute myeloid leukemia (AML) soon after their initial diagnosis, contributing to the poor prognosis of CMML patients. During the prior funding period, we collaborated with the International MDS/MPN Consortium and demonstrated that concurrent NRAS and ASXL1 mutations define a population of CMML patients with shorter leukemia-free survival than those with ASXL1 mutations only. Based on our human data, we characterized NrasG12D/+; Asxl1-/- (NA) mice that model CMML patients with concurrent NRAS and ASXL1 mutations. NA mice developed CMML with accelerated progression and in ~50% of these mice CMML transformed to AML (secondary AML, sAML). NA leukemia cells exhibited hyperactivation of MEK/ERK signaling and increased global level of H3K27Ac, a histone mark bound by bromodomain and extra-terminal domain (BET) proteins for gene transcriptional activation. Upregulation of AP-1 transcription factors (TFs) mediated the overexpression of PD-L1 and CD86, two inhibitory immune checkpoint ligands, and helped establish a suppressive immune microenvironment in NA-sAML recipients. Combined inhibition of MEK and pan-BET proteins led to downregulation of AP-1 TF expression, partial mitigation of the suppressive immune microenvironment, enhancement of CD8 T cell cytotoxicity, and prolonged survival in NA-sAML mice. Based on our preliminary results, we hypothesize that Asxl1-/- and oncogenic Nras cooperate to accelerate CMML and promote its transformation to AML via reprogramming the immune microenvironment, which includes but may not limit to T cells. Moreover, immunomodulatory agents may further improve the therapeutic benefits of combine MEK and BET inhibition through establishing durable anti-leukemia activities in immune cells. In this renewal application, we propose the following two aims to test our hypothesis: 1) To identify the molecular and cellular mechanisms underlying the dysregulation of immune microenvironment in in NA mice; and 2) determine whether immunomodulatory agents further improve the therapeutic effects of combined MEK and BET inhibition in NA mice. Together, our proposed studies will not only provide fundamental perspectives on disease mechanisms but also test hypotheses that could potentially lead directly to potent and efficacious novel therapies for treating CMML and transformed AML.


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: 2025 ( Subtotal = $406,245 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Biology Research	001	13	5/30/2025	NON-COMPETING CONTINUATION	$40,623
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Biology Research	000	13	3/19/2025	NON-COMPETING CONTINUATION	$365,622
														Subtotal = $406,245

Issue Date FY: 2024 ( Subtotal = $385,932 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Biology Research	002	12	4/17/2024	NON-COMPETING CONTINUATION	$20,310
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Biology Research	001	12	3/29/2024	NON-COMPETING CONTINUATION	$365,622
2024	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Biology Research	000	10	3/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $385,932

Issue Date FY: 2023 ( Subtotal = $406,245 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Biology Research	000	11	4/14/2023	COMPETING CONTINUATION	$406,245
														Subtotal = $406,245

Issue Date FY: 2021 ( Subtotal = $370,624 )
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cancer Biology Research	000	10	2/25/2021	NON-COMPETING CONTINUATION	$364,812
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cancer Biology Research	001	10	9/3/2021	NON-COMPETING CONTINUATION	$5,812
														Subtotal = $370,624

Issue Date FY: 2020 ( Subtotal = $568,895 )
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cancer Biology Research	000	9	3/6/2020	NON-COMPETING CONTINUATION	$568,895
														Subtotal = $568,895

Issue Date FY: 2019 ( Subtotal = $569,640 )
2019	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cancer Biology Research	001	8	4/3/2019	SUPPLEMENT FOR EXPANSION	$215,707
2019	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cancer Biology Research	000	8	2/4/2019	NON-COMPETING CONTINUATION	$353,933
														Subtotal = $569,640

Issue Date FY: 2018 ( Subtotal = $373,634 )
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cancer Biology Research	001	7	1/24/2018	NON-COMPETING CONTINUATION	$329,038
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cancer Biology Research	003	7	7/27/2018	NON-COMPETING CONTINUATION	$8,035
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cancer Biology Research	002	7	5/23/2018	NON-COMPETING CONTINUATION	$36,561
2018	2015	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cancer Biology Research	000	5	1/23/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $373,634

Issue Date FY: 2017 ( Subtotal = $378,849 )
2017	2017	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cancer Biology Research	001	6	3/1/2017	COMPETING CONTINUATION	$378,849
2017	2015	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cancer Biology Research	000	5	3/1/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $378,849

Issue Date FY: 2015 ( Subtotal = $312,288 )
2015	2015	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Cancer Biology Research	000	5	6/26/2015	NON-COMPETING CONTINUATION	$312,288
														Subtotal = $312,288

Issue Date FY: 2014 ( Subtotal = $321,500 )
2014	2014	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Cancer Biology Research	000	4	7/3/2014	NON-COMPETING CONTINUATION	$302,919
2014	2014	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Cancer Biology Research	001	4	8/5/2014	NON-COMPETING CONTINUATION	$18,581
														Subtotal = $321,500

Issue Date FY: 2013 ( Subtotal = $300,551 )
2013	2013	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Cancer Biology Research	000	3	7/30/2013	NON-COMPETING CONTINUATION	$293,551
2013	2013	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Cancer Biology Research	001	3	9/20/2013	NON-COMPETING CONTINUATION	$7,000
														Subtotal = $300,551

Issue Date FY: 2012 ( Subtotal = $325,788 )
2012	2012	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Cancer Biology Research	001	2	8/1/2012	NON-COMPETING CONTINUATION	$312,288
2012	2012	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Cancer Biology Research	002	2	9/14/2012	NON-COMPETING CONTINUATION	$10,000
2012	2012	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Cancer Biology Research	000	1	7/10/2012	SUPPLEMENT FOR EXPANSION	$3,500
														Subtotal = $325,788

Issue Date FY: 2011 ( Subtotal = $312,288 )
2011	2011	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Cancer Biology Research	000	1	9/2/2011	NEW	$312,288
														Subtotal = $312,288

Grand Total All Awards = $5,032,479

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Molecular and Cellular Mechanisms of Chronic Myelomonocytic Leukemia (CMML)

Award Number: R01CA152108

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/02/2011

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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