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Unraveling the impact of NUP98-HOXA9 on DNA damage responses

Award Number: R21ES038781
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/09/2026
PERIOD OF PERFORMANCE END DATE: 06/08/2028

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Unraveling the impact of NUP98-HOXA9 on DNA damage responses - SUMMARY DNA double-strand breaks (DSBs) occur in every cell as a result of exposure to environmental mutagens, such as ionizing radiation, chemotherapeutic drugs, ultraviolet light, and toxic pollutants, as well as in response to normal cellular activities, such as DNA replication. Defective DSB repair is a major driver of genome instability, contributing to cancer initiation, progression and recurrence. Repairing DSBs is particularly challenging in pericentromeric heterochromatin because this genomic region is mostly composed of repeated sequences that are prone to aberrant recombination. Faithful heterochromatin repair requires a specialized pathway that moves repair sites and their templates away from the bulk of repeated sequences before the strand invasion step of homologous recombination (HR) repair. This spatial reorganization prevents ectopic recombination while promoting accurate repair. A key regulator of this pathway is the nucleoporin NUP98, which operates “off pore” in this context. NUP98 is recruited to heterochromatic DSBs, where it halts HR progression while promoting relocalization, and this function depends on its phase separation properties. Strikingly, NUP98 is involved in over 30 distinct protein fusions responsible for leukemia, including NUP98-HOXA9, a common cause of pediatric acute myeloid leukemia (AML). In this chimeric protein, the N-terminus of NUP98 is joined to the C-terminus of the homeodomain-containing transcription factor A9 (HOXA9). NUP98-HOXA9 is linked to aggressive, treatment-resistant forms of leukemia, particularly pediatric cancer. Understanding how NUP98-HOXA9 impacts heterochromatin repair is essential for establishing how this malignancy originates and progresses, and for informing new therapeutic strategies. Both the phase separation properties of NUP98-HOXA9 and the dysregulation of HOXA9 targets are critical for leukemic transformation. However, how NUP98-HOXA9 affects the DNA damage response remains unknown. Our central hypothesis is that NUP98-HOXA9 is aberrantly recruited to heterochromatin repair sites, where it interferes with the biophysical properties of repair condensates while also inducing the leukemic transcriptional reprogramming. This compounded effect may promote abnormal cell division and block differentiation while inducing genome instability, contributing to disease onset. We will test these hypotheses using mouse leukemia cell models. We expect these studies will define new functions of NUP98 fusion proteins, elucidating their impact on genome organization, transcriptional regulation, and heterochromatin repair. Ultimately, we anticipate this work will reveal fundamental mechanisms by which environmental factors affect genome integrity, offering new insights into the environmental origins of leukemias and identifying potential targets for prevention and intervention.


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 = $452,547 )
2026	2026	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Environmental Health	000	1	6/9/2026	NEW	$452,547
														Subtotal = $452,547

Grand Total All Awards = $452,547

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Unraveling the impact of NUP98-HOXA9 on DNA damage responses

Award Number: R21ES038781

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/09/2026

PERIOD OF PERFORMANCE END DATE: 06/08/2028

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