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Tracing the lineage histories and differentiation trajectories of individual cancer cells in myeloproliferative neoplasms

Award Number: R01HL158269
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary In some cancers, intriguingly, the same mutation results in drastically different disease phenotypes in different patients. An example is a type of blood cancer, known as myeloproliferative neoplasm (MPN), where a single nucleotide change in the JAK2 gene, may result in either an increase in the number of red blood cells, an increase in the number of platelets, or scarring of bone marrow tissue, in different patients. The disease outcome is just as unpredictable. Some patients show no symptoms for decades whereas others rapidly progress to acute leukemias. This disconnect between genotype and phenotype may be due to the identity of the hematopoietic stem cell (HSC) in which the mutation first occurs. Not all HSCs are equivalent and some may preferentially give rise to certain types of blood cells. Additionally, the subsequent expansion of the population of mutated stem cells may be different in different patients. Therefore, to understand the heterogeneity in disease presentation, we would like to know when and in which cell the cancer mutation first occurred in each patient, how the population of mutated HSCs expanded, and to what extent the differentiation trajectory of the cancer cells deviates from that of the healthy cells. Here, we propose a comprehensive research program to make these measurements in individual MPN patients. To understand the difference between the cancer cells and the healthy cells in each patient, we will profile each cell individually. Bulk measurements average over the cancer cells and healthy cells, and obscure different cell states along the differentiation trajectory. We have recently developed a technology platform to simultaneously read out the full transcriptome and the cancer mutation in single cells. We will apply this platform to cells obtained from bone marrow biopsies of MPN patients. To obtain the history of the expansion of the cancer stem cells in each patient, we will reconstruct the lineage tree of the HSCs by sequencing the somatic mutations in the whole genomes of individual HSCs. Somatic mutations occur randomly at each cell division and are passed on to a cell’s descendants. Critically, we will also trace the differentiation trajectories of the progenies of each HSC by identifying the somatic mutations that uniquely mark each HSC in our single-cell transcriptomic data. Taken together, these measurements will provide the most detailed molecular picture of MPN at a single-cell resolution and the most comprehensive molecular history of cancer progression in individual patients. Finally, to identify and test potential therapies for MPN, we will engineer animal models whereby lineage histories of individual cells can be obtained without whole genome sequencing. We will engineer a mouse model of MPN in which individual cells record their lineage histories in their own DNA by using Cas9 to induce heritable mutations in synthetic target arrays that are transcribed and read out using sequencing. Our proposal will answer some of the most outstanding and fundamental questions about MPNs and blood development. Ultimately, our measurements should reveal patient-specific targeted therapies that preferentially eradicate the cancer stem cells or hinder their differentiation.


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 = $442,500 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Blood Diseases and Resources Research	000	5	1/17/2025	NON-COMPETING CONTINUATION	$442,500
														Subtotal = $442,500

Issue Date FY: 2024 ( Subtotal = $525,485 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Blood Diseases and Resources Research	001	4	3/29/2024	SUPPLEMENT FOR EXPANSION	$82,985
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Blood Diseases and Resources Research	000	4	1/8/2024	NON-COMPETING CONTINUATION	$442,500
														Subtotal = $525,485

Issue Date FY: 2023 ( Subtotal = $442,500 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	3	5/30/2023	NON-COMPETING CONTINUATION	$442,500
														Subtotal = $442,500

Issue Date FY: 2022 ( Subtotal = $442,500 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	001	2	6/15/2022	NON-COMPETING CONTINUATION	$44,250
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	1/13/2022	NON-COMPETING CONTINUATION	$398,250
														Subtotal = $442,500

Issue Date FY: 2021 ( Subtotal = $442,500 )
2021	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	1	1/8/2021	NEW	$398,250
2021	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	001	1	6/14/2021	NEW	$44,250
														Subtotal = $442,500

Grand Total All Awards = $2,295,485

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Tracing the lineage histories and differentiation trajectories of individual cancer cells in myeloproliferative neoplasms

Award Number: R01HL158269

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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