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Sphingolipid-guided stratification and therapeutic opportunities in Acute Myeloid Leukemia

Award Number: K22CA299417
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/08/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Sphingolipid-guided stratification and therapeutic opportunities in Acute Myeloid Leukemia - PROJECT SUMMARY Acute myeloid leukemia (AML) has been extensively characterized at the genomic level yielding many genomic classifications. However, there is a mismatch between genomic risk and clinical outcomes, and a majority of patients lack known genomic features. Thus, there is an urgent need to improve AML risk classification beyond genomics informing effective AML therapeutics for patients who otherwise lack targetable alternatives. Accumulating evidence link AML pathogenesis to dysfunctional sphingolipid metabolism. Sphingolipids are a family of several bioactive molecules delicately balanced to maintain cellular functions. My recent work has identified two sphingolipid subtypes in AML patient cases and cells. These subtypes show reciprocal abundance of hexosylceramide and sphingomyelin species (HexhighSMlow & HexlowSMhigh) and are: (i) robust for patient and cell lines, (ii) linked to latent transcriptional states, and (iii) predictive of patient outcomes in multiple datasets. Notably, the HexlowSMhigh subtype represents a high-risk group with unfavorable outcomes, confirming the utility of sphingolipids in refining the AML risk assessment, offering therapeutic opportunities. The study raises new questions into the signaling states and mechanisms that drive the two subtypes, and specific therapeutic vulnerabilities. Preliminary data indicate a role of transcription factor, STAT5A in driving the high-risk HexlowSMhigh subtype which is correlated to drug response to several class of inhibitors. Recent findings suggest that sphingolipid enzymes regulate STAT5 activity in leukemias, where ceramides serve as a cellular second messenger indicating positive feedback between sphingolipids and activity of STAT5. One mechanism regulating STAT5A activity is its phosphorylation and subsequent translocation from the cytoplasm to the nucleus. Nuclear importins and exportins are altered by several sphingolipid species and enzymes. Nuclear importins, mainly importinβ is significantly higher in the HexlowSMhigh subtype. These variabilities may thus result in sphingolipid- specific nucleocytoplasmic shuttling states, with differential localization of key proteins. Although transport inhibitors are effective in hematologic malignancies, their success in AML has been modest, likely due to the heterogeneity in these shuttling states. Thus, I hypothesize that distinct STAT5A-mediated signaling and nucleocytoplasmic shuttling states result from sphingolipid heterogeneity in AML. I will use experiments, and computational and statistical modeling to link sphingolipid-subtype-specific differences to STAT5A-mediated biochemical signaling states in AML (Aim 1) and to determine nucleocytoplasmic transport capacity and predict responses to nuclear export inhibitors across AML samples in the two sphingolipid clusters (Aim 2). Together, I aim to study how sphingolipid composition impacts nucleocytoplasmic shuttling and identify therapeutic vulnerabilities specific to sphingolipid subtypes in AML. My training plan in this transition award will establish a foundation for my independent research plan integrating quantitative mechanistic pharmacology and cancer biology to understand emergent cancer phenotypes.


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 = $192,887 )
2026	2026	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Research Manpower	000	1	5/12/2026	NEW	$192,887
														Subtotal = $192,887

Grand Total All Awards = $192,887

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Sphingolipid-guided stratification and therapeutic opportunities in Acute Myeloid Leukemia

Award Number: K22CA299417

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/08/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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