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Crosstalk between leukemic blasts and the BM microenvironment contribute to leukemic transformation

Award Number: R01CA259182
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/04/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Crosstalk between leukemic blasts and the BM microenvironment contribute to leukemic transformation - PROJECT SUMMARY Acute myeloid leukemia (AML) is a clonal, highly heterogeneous malignancy of the blood and bone marrow with poor prognosis. Along with genetic mutations within the leukemic cells themselves, alterations in the BM microenvironment (BMM) also play an important role in leukemia transformation, therapy resistance, and relapse. Thus, to develop effective AML therapies, it is critical to understand how intrinsic genetic alterations in the leukemic blasts cooperate with the BMM to facilitate leukemogenesis. We identified that the secreted protein Epithelial Growth Factor Like 7 (EGFL7) is highly expressed in a large cohort of AML patients and is associated with poor prognosis. We further demonstrate that: 1) EGFL7 protein increases blast cell growth and impacts on leukemic stem cell (LSC) function; 2) leukemic bone marrow mesenchymal stromal cells (MSCs) express and secrete EGFL7 at increased levels compared to normal MSCs ; 3) normal MSCs exhibit increased growth and survival in response to a recombinant EGFL7 protein and 4) Egfl7 is increased in AML blasts, but not in pre- leukemic hematopoietic stem and progenitor cells (HSPCs) from a primary Mll PTD; Flt3 ITD murine AML model. Based on our work, we hypothesize that aberrant EGFL7 expression by leukemic cells and BM niche cells contribute to leukemogenesis and is a relevant target for treatment for AML patients. The goal of our proposal is to fully characterize the phenotypic contributions of EGFL7 to myeloid leukemogenesis, dissect its molecular mechanism(s), and determine the therapeutic benefit of targeting EGFL7 in AML. We are planning to achieve these goals through the following specific aims (SA): SA#1: To demonstrate the importance of EGFL7 in leukemic cells to alter the BM microenvironment to promote leukemogenesis. Here, we hypothesize that EGFL7 promotes a positive feedback loop between leukemic cells and the BM microenvironment contributing to disease initiation and progression. We will test this hypothesis with a series of in vitro and in vivo experiments organized in three tasks. In Task 1 we will examine the contribution of EGFL7 in the BMM towards the initiation of AML using our Mll PTD; Flt3 ITD and Egfl7fl/fl conditional knock-out mouse models. For Task 2 we will determine how alterations in the expression of EGFL7 effects MSCs in leukemogenesis. Task 3 we will characterize the molecular mechanisms of Egfl7-dependent signaling pathways in MSCs; SA#2: To investigate anti-leukemic activity of a monoclonal EGFL7 blocking antibody (Parsatuzumab) in combination with a FLT3 inhibitor (Gilteritinib), using patient derived xenograft (PDX) murine models and primary genetic murine models of AML. Here, we propose to conduct in vitro and in vivo preclinical studies using AML cell lines, primary AML samples and two murine models of FLT3 mutated AML to evaluate the efficacy of targeting the autocrine and paracrine action of EGFL7 in AML. Overall, this proposal seeks to define the role of EGFL7 in the cross-talk between the BMM and leukemic cells and to generate preclinical data to support clinical development of anti-EGFL7 monoclonal antibodies in combination with FLT3 inhibitors for FLT3 mutated 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: 2026 ( Subtotal = $361,647 )
2026	2026	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	5	2/26/2026	NON-COMPETING CONTINUATION	$361,647
														Subtotal = $361,647

Issue Date FY: 2025 ( Subtotal = $361,374 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	002	4	5/22/2025	NON-COMPETING CONTINUATION	$36,138
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	001	4	2/14/2025	NON-COMPETING CONTINUATION	$325,236
2025	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	000	2	1/16/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $361,374

Issue Date FY: 2024 ( Subtotal = $325,196 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	001	3	3/5/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$325,196
2024	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	000	2	3/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $325,196

Issue Date FY: 2023 ( Subtotal = $357,254 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	000	2	2/27/2023	NON-COMPETING CONTINUATION	$357,254
														Subtotal = $357,254

Issue Date FY: 2022 ( Subtotal = $368,485 )
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	000	1	3/4/2022	NEW	$368,485
														Subtotal = $368,485

Grand Total All Awards = $1,773,956

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Crosstalk between leukemic blasts and the BM microenvironment contribute to leukemic transformation

Award Number: R01CA259182

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/04/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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