Novel regulation of oncogenic nras signaling in myeloid malignancies

Active Project Grant Awarded Last action

Award ID
R01CA271523
Recipient
Awarding agency
Obligated
$5,815,051

Award facts

Assistance listing
93.396 Cancer Biology Research
Completion date 92% complete
Place of performance
Philadelphia, PA 19104, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Hematopoietic stem and progenitor cells (hspcs) are regulated by a balanced signaling network, which is critical for hspc homeostasis and prevention of malignant transformation. We previously showed that protein ubiquitination by CBL family E3 ubiquitin ligases controls JAK2 stability and activity that is important for curbing hspc expansion and myeloid malignancies. Here we identified a novel signaling axis, where CBL/JAK2 upregulates RAB27B to enhance nras gtpase activity and ERK signaling. Importantly, aberrant activation of this pathway is critical for leukemia cell growth conferred by CBL and RAS mutations. Intracellular signaling can be dynamically modulated by post-translational modifications (ptms) that regulate the temporal and spatial distribution of signaling proteins. RAB27B, a RAB gtpase that is resident in the golgi and endosome membranes, regulates intracellular vesicle trafficking, docking, and fusion with plasma membrane (PM). RAB27B knockout mice display normal steady-state hematopoiesis. Strikingly, we found that RAB27B deficiency in primary hspcs abrogates mutant but not wildtype nras-mediated signaling and cell growth. Mechanistically, we demonstrated that RAB27B regulates nras palmitoylation, gtpase activity, stability, and subsequent c- RAF/MEK/ERK activation. RAS proteins propagate signals only when associated with cellular membranes as a consequence of various ptms that impact their trafficking between endomembranes and the PM. Therefore, a precise understanding of RAS' interaction with membranes and trafficking is essential to understand RAS action and to intervene in RAS-driven cancers. The discovery of RAB27B as a novel regulator of RAS palmitoylation, a lipid modification for membrane anchors, propelled US to further define the molecular basis underlying the regulation of RAS/ERK signaling by CBL/JAK2/RAB27B and explore its functional significance in malignant hspcs. In aim 1, we will investigate if RAB27B deficiency mitigates chronic myelomonocytic leukemia (cmml) development and malignant hspc expansion induced by mutant nras or CBL deficient mice. More importantly we will study if RAB27B deficiency dampens nras signaling, stability, lipid modification and subcellular localization. In aim 2, we will use live-cell imaging and biochemical assays as well as genetic approaches, to dissect the dynamic regulation of nras trafficking, palmitoylation, and compartmentalized signaling by RAB27B. In aim 3, we will investigate the role of mutant CBL/JAK2 in regulating RAB27B level and explore the therapeutic potential of targeting RAB27B in primary hspcs from human myeloid malignancies. RAS pathway mutations including nras and CBL define the proliferative cmml (pcmml) phenotype that is aggressive, predisposed to AML transformation and associated with dismal outcomes. This work uncovers novel RAB27B-mediated compartmentalized signaling dynamics that is crucial to key signaling proteins, and serves the basis for future therapeutic strategies for molecular targeting.

Transactions

Action Obligated Date
Amendment $547,313
Amendment $54,731
Amendment $492,582
Amendment $492,582
Amendment $27,367
Amendment $27,367
Amendment $27,367
Amendment $492,582
Amendment $492,582
Amendment $492,582
Amendment $492,582
Amendment $536,367
Amendment $536,367
Amendment $536,367
Original award $566,313
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Subawards

Subrecipient Amount Awarded
New York University Dr. Philips is an internationally recognized expert in the post-translational modification and subcellular trafficking of RAS proteins, which is a central focus… $210,156
New York University $42,628
New York University $40,497

Quick answers

Who received award R01CA271523?

R01CA271523 was awarded to The Children's Hospital Of Philadelphia by National Cancer Institute (National Institutes of Health) on April 1, 2022.

How much is award R01CA271523 worth?

$5,815,051 has been obligated on R01CA271523.

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