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Targeting dormant leukemia-initiating cells in T-cell acute lymphoblastic leukemia

Award Number: F30CA257270
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/23/2020
PERIOD OF PERFORMANCE END DATE: 12/22/2024

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Targeting dormant leukemia-initiating cells in T-cell acute lymphoblastic leukemia - PROJECT SUMMARY/ABSTRACT Therapy resistance is a major barrier to long term remission in pediatric T-cell acute lymphoblastic leukemia (T- ALL). The prognosis for children with relapsed or refractory disease is dismal. Leukemia-initiating cells (L-ICs) regenerate disease upon transplantation into mice. They also recapitulate the immunophenotypic complexity of the parent leukemia supporting that, as in normal hematopoiesis, there is a cellular hierarchy among leukemic cells. Our laboratory has previously demonstrated that the L-IC is a committed thymocyte progenitor and resides in the leukemic DN3 population, however, only a fraction of DN3 cells can give rise to disease. L-ICs rely on NOTCH1-induced MYC signaling for survival. Recent studies identified dormant, therapy resistant L-ICs in both murine models and T-ALL patient samples. The role of cell cycle restriction in L-IC latency is incompletely understood. In an effort to uncover pathways that govern L-IC function, we performed single cell RNA- sequencing on thymocytes at varying stages of T-cell leukemogenesis using our transgenic Tal1/Lmo2 model. This approach identified a dormant DN3 cluster, marked by low Ki67 expression, which is observed in other murine T-ALL samples. Dormant DN3 cells exhibit high Notch1, but low Myc expression. The transcriptional signature of these cells shows enrichment of genes previously implicated in leukemia initiation or leukemia stem cell function. Dormant DN3 cells show enrichment of the non-canonical Wnt receptor Ryk, which is reported to maintain hematopoietic stem cell self-renewal by limiting proliferation and promoting quiescence. RYK is overexpressed in primary pediatric T-ALL and in Tal1/Lmo2-induced murine T-ALL compared to healthy thymus. This indicates that RYK may not be restricted to this rare subpopulation and moreover, there may be a therapeutic window for RYK inhibition in relapsed T-ALL. The central hypothesis of this proposal is that dormant DN3 cells are quiescent L-ICs that retain proliferative and differentiative capacity, which permits their therapy tolerance and subsequent expansion during relapse. This proposal will identify a gene signature of dormant DN3 cells and uncover the potential role of these cells in T-ALL relapse by evaluating their L-IC function and chemoresistance (Aim 1). Aim 2 will define the non-canonical WNT/RYK signaling network in T-ALL and uncover the role of these pathways in dormant DN3 cells and L-IC function by testing whether inhibition of RYK reduces the L-IC frequency of murine and patient T-ALL cells. Collectively, these studies will provide critical insight to T- ALL heterogeneity and will lay the foundation for development of L-IC targeted therapy for relapsed disease.


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 = $50,649 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Cancer Research Manpower	000	4	12/4/2023	NON-COMPETING CONTINUATION	$49,369
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Cancer Research Manpower	001	4	5/7/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $50,649

Issue Date FY: 2023 ( Subtotal = $34,852 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Cancer Research Manpower	001	3	5/22/2023	NON-COMPETING CONTINUATION	$942
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Cancer Research Manpower	000	3	11/2/2022	NON-COMPETING CONTINUATION	$33,910
														Subtotal = $34,852

Issue Date FY: 2022 ( Subtotal = $33,910 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Cancer Research Manpower	001	2	5/27/2022	NON-COMPETING CONTINUATION	$716
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Cancer Research Manpower	000	2	12/9/2021	NON-COMPETING CONTINUATION	$33,194
														Subtotal = $33,910

Issue Date FY: 2021 ( Subtotal = $33,194 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Cancer Research Manpower	000	1	12/23/2020	NEW	$32,678
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Cancer Research Manpower	002	1	2/2/2021	NEW	$0
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Cancer Research Manpower	001	1	2/2/2021	NEW	$516
														Subtotal = $33,194

Grand Total All Awards = $152,605

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Targeting dormant leukemia-initiating cells in T-cell acute lymphoblastic leukemia

Award Number: F30CA257270

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/23/2020

PERIOD OF PERFORMANCE END DATE: 12/22/2024

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