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3219 Somatic Genetic Rescue Involving CSF3R and Other Novel Phosphothyrosine Kinase Receptor Mutations Occurring in Myeloid Malignancies

Program: Oral and Poster Abstracts
Session: 636. Myelodysplastic Syndromes—Basic and Translational: Poster II
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, Translational Research, genomics, Diseases, Myeloid Malignancies, Biological Processes, Technology and Procedures, pathogenesis
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Serhan Unlu, MD1*, Christopher Haddad2*, Danai Dima, MD3, Tariq Kewan, MBBChir4, Olisaemeka Ogbue1, Waled Bahaj, MD5, Carlos Bravo-Perez, MD1*, Luca Guarnera, MD1*, Yasuo Kubota, MD, PhD6*, Hetty E. Carraway, MD, MBA7, Carmelo Gurnari, MD1*, Seth J Corey, MD8, Hrishikesh Mukesh Mehta, PhD9*, Valeria Visconte, PhD1 and Jaroslaw P. Maciejewski, M.D., Ph.D., FACP1

1Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
2Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Westlake, OH
3Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
4Yale Cancer Center, Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT
5Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH
6Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Beachwood, OH
7Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH
8Departments of Pediatrics and Cancer Biology, Cleveland Clinic, Cleveland, OH
9Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH

Somatic gene rescue (SGR), via acquisition and selection of somatic (SM) genetic hits, neutralizes functional defects resulting from hypomorphic germline (GL) mutations. However, this process may be maladaptive and lead to the development of leukemia. Acquisition of SM gain-of-function CSF3R mutations in the context of severe congenital neutropenia (SCN) illustrates such a scenario. Here, we further explored this and similar mechanisms in a cohort of 7121 adults with myeloid neoplasia and bone marrow failure (AML=1473, MDS=2248, other=3400). CSF3R mutations were found in 97 patients. In total, there were 37 and 56 patients with SM and GL mutations, respectively; biallelic GL and SM were 4. Among SM alterations, 18 were pathogenic or likely pathogenic including 8 nonsense truncating variants in class III isoform specific region of the cytoplasmic domain and 10 classical missense mutations in the juxtamembrane region, previously defined in the context of post-SCN AML and CNL.

We thus hypothesized that these CSF3RSM mutations may also represent SGR in adult patients harboring hypomorphic GL variants and investigated the presence of SCN-associated alterations (ELANE, WAS, GFI1) and in other phosphothyrosine kinase receptors (PTKR) such as CSF1R, CSF2RA, CSF2RB, FLT3, and KIT.

Indeed, we found biallelic WAS p.D264HGL and CSF3R p.A119TSM in a patient with aplastic anemia (AA). Biallelic CSF3R were present in 4 patients: a) p.Q749XGL with p.M696TSM, b) E835KGL with p.T618ISM, c) p.Y752XGL with p.Q754ESM and d) biallelic p.Y752XGL with p.Q754EGL configuration with T615ASM.

Compound heterozygous configuration of CSF3RSM included CSF1RSM variants (CSF3R p.M696TSM & CSF1R p.R294QGL in a 64 year old. patient with MPN, CSF3R p.M696TSM & CSF1R c.1626+3G>AGL in a 61 year old patient with MDS) and CSF2RB (CSF3R p.T618ISM & CSF2RB p.V890IGL in a 69 year old female patient with AML with leukopenia).

When we analyzed the remaining 66 GL CSF3R variants in 56 carriers (in addition to the aforementioned biallelic combinations), we identified 9 compound heterozygous mutants involving CSF1RSM (n=1), CSF2RA (n=1), CSF2RB (n=3), FLT3 (TKD/ITD, n=4/1). Specifically, we found the following configurations and disease associations: a) CSF3R p.V372EGL CSF2RB p.P842LSM in a 49 yo. AA patient who subsequently developed AML with FLT3TKD, b) MDS patients with CSF3R p.E149GL CSF1R p.G413SSM, c) CSF3R p.R440QGL & CSF2RA p.R164QSM and d) CSF3R p.E405KGL & CSF2RB c.1152+6G>ASM and e) AML patients with CSF3R p.E405KGL & CSF2RB p.R432CSM; f) CSF3R p.L619SGL and g,h) 2 AML cases with CSF3R p.E808KGL of which all 3 acquired compound heterozygosity with FLT3TKD, i) CSF3R p.E808KGL CSF3R p.E835KGL in a 71 year old patient with MDS with FLT3ITD AML. In addition to FLT3 GOF mutations, the most common SM hits observed in CSF3RGL carriers were ASXL1 (n=12), TET2 (n=12), and SF3B1 (n=12).

Identification of somatic and GL alterations in PTKR genes other than CSF3R, led us to systematically analyze these genes as targets of GL and SM CSF3R alterations. In total, we identified 72 GL and 73 SM CSF1R variants, 7 SM and 19 GL CSF2RA and 47 GL and 69 SM CSFR2B. Among these, we found 3 patients with compound heterozygous CSF2RBSM CSF3RGL, one with CSF2RBGL CSF3RGL as described above. We also identified one patient with CSF2RASM CSF3RGL. Finally, we identified two patients with CSF1RGL and CSF3RSM, and one with CSF1RSM CSF3RGL mutations.

In summary, our study provides evidence for a tremendous complexity of interaction between less penetrant GL alterations of receptor genes and somatic GOF mutations, which may in some instances, correspond to the result of SGR. It is likely that the degree of LOF corresponds to the selection pressure for somatic rescue lesions.

Disclosures: Carraway: Jazz Pharmaceuticals: Consultancy, Other: Travel, Accommodations, Expenses , Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; AbbVie: Other; Daiichi: Consultancy; Celgene: Research Funding; Agios: Consultancy, Speakers Bureau; Takeda: Other; Stemline Therapeutics: Consultancy, Speakers Bureau; Genentech: Consultancy; Astex Pharmaceuticals: Other; Syndax: Other: DSMB; Novartis: Consultancy, Other: Travel, Accommodations, Expenses , Speakers Bureau. Maciejewski: Novartis: Honoraria, Speakers Bureau; Omeros: Consultancy; Regeneron: Consultancy, Honoraria; Alexion: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH