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4336 Molecular Landscape of c-CBL Mutation in Adults’ Myeloid Malignancies

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Poster III
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, MDS, Translational Research, MPN, CML, Chronic Myeloid Malignancies, CMML, Diseases, Myeloid Malignancies, Biological Processes, pathogenesis
Monday, December 11, 2023, 6:00 PM-8:00 PM

Luca Guarnera, MD1,2*, Carmelo Gurnari, MD1,2, Carlos Bravo-Perez, MD1,3*, Arda Durmaz1*, Nakisha D Williams, MBBS1*, Hussein Awada1*, Naomi Kawashima, MD, PhD1*, Arooj Ahmed, MD1*, Serhan Unlu, MD1*, Christopher Haddad1*, Aashray Mandala, BS1*, Yasuo Kubota, MD, PhD4*, Jaroslaw P. Maciejewski, M.D., Ph.D., FACP1 and Valeria Visconte, PhD1

1Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
2Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
3Department of Hematology and Medical Oncology, Hospital Universitario Morales Meseguer, University of Murcia, IMIB-Pascual Parrilla, CIBERER - Instituto de Salud Carlos III, Murcia, Spain
4Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Beachwood, OH

Background: CBL proteins are a family of RING finger (RF) E3 ubiquitin ligases that regulate proliferative signals via ubiquitination and degradation of tyrosine-phosphorylated signaling protein (e.g., FLT3, JAK2, MPL). Thus, the loss of CBL activity due to hypomorphic or loss of function (LOF) mutations functionally may result in oncogenic effects. However, simple LOF does not explain the high rates of c-CBL (most abundant CBL isoform, located on chromosome 11) missense mutations affecting a canonical position in the RF domain, catalytic region responsible for ubiquitin ligase activity.

We hypothesized that studying the molecular and clinical associations of c-CBL mutations will help clarifying the consequences of its mutations and conceptualize innovative treatment strategies.

Methods: We analyzed molecular and clinical features of a cohort of 11036 patients with myeloid neoplasia (MN; 63% AML, 29% MDS, 5% MPN/MDS, 3% MPN) from The Cleveland Clinic Foundation and public series. Clonal burden of c-CBL was analyzed to infer clonal hierarchy and to establish founder vs secondary mutations based on our previously described criteria.

Results: Overall, c-CBL mutations were detected in 2.4% (270/11036) of the patients. The most common c-CBL mutations were missense (80%) and mainly occurred in the RF domain and linker region (83% of mutations, Fig1).

c-CBL mutations were found in 2% of both primary AML (pAML; 3% of CBF) and sAML/HR-MDS and 8% of CMML. Among CMML patients, mutations were associated with low-risk features (7% of CMML2 vs. 13% of CMML1). The most frequent co-associated mutations were TET2 (22%) and RUNX1 (19%) in all AML, ASXL1 (50%), SRSF2 (25%) and TET2 (25%) in MDS, and ASXL1 (50%), SRSF2 (44%) and JAK2 (28%) in MPN and MPN/MDS.

In terms of associations with tyrosine kinase receptors (FLT3, c-KIT, CSF3R, c-MPL), we found that 18% of c-CBL mutants carried at least one mutation in one the four receptors, contrarily to what expected from previously reported results of c-CBL/FLT3 mutational exclusivity.

In most of the cases, c-CBL mutations were subclonal (53%), arguing against its primary driver/initiator function. Indeed, we observed c-CBL mutations as the only lesion in 7% of the cases with no specific disease association (66%, AML; 25%, LR-MDS; 8%, CMML).

There was no difference in MN phenotypes between carriers of canonical vs non canonical c-CBL mutations; however, we found that non canonical mutations were more often ancestral or the only founder lesion detected compared to canonical mutations (46 vs 31%, P = 0.031).

Del(11q) or monosomy 11 were found in 8 patients, without association with c-CBL VAF >50%. Furthermore, c-CBL VAF>50% was not associated with marrow blast infiltrate, WBC or shorter survival.

We then analyzed the effect of c-CBL in cooperation with RAS genes (NRAS, KRAS, PTPN11, NF1) and found that, in AML, the effect of c-CBL with 2 RAS genes (5 patients, 3%) showed some trends toward higher blast count (P = 0.079), higher WBC (P = 0.076) and lower rates of normal cytogenetics compared to the effect of the remaining c-CBL mutant (0 vs 48%, P = 0.061).

Conclusions: In sum, our study of the molecular landscape of c-CBL mutations highlights that these lesions occur mainly during disease development with majority of the cases carrying subclonal hits with a weaker effect on disease phenotype and prognosis. Such mutations can be present in both primary and secondary AML (in contrast with previous reports) and additive effects can be observed when c-CBL mutations co-occur with more than one RAS gene in these disease groups. In some cases, especially in non-canonical mutations, c-CBL could also act as ancestral event and as an independent leukemic driver.

Disclosures: Maciejewski: Regeneron: Consultancy, Honoraria; Alexion: Membership on an entity's Board of Directors or advisory committees; Omeros: Consultancy; Novartis: Honoraria, Speakers Bureau.

*signifies non-member of ASH