Maladaptive Somatic Rescue in FLT3 Mutations of Suspected Germline Nature

Somatic genetic rescue (SGR) is a very rare process in which the occurrence of a somatic genetic event offsets the consequences of a germline (GL) mutation resulting in genetic mosaicism and, in some cases, in a milder disease phenotype ¹. Acquired somatic mutations may be adaptive by countering the negative effects of the primary mutation ( e.g., improving hematopoiesis) or maladaptive by overcorrecting the initial impairment causing a different, possibly opposite, disease phenotype ( e.g., leading to the development of a myeloid malignancy) ². Exemplary cases of the latter scenario are mainly represented by severe congenital neutropenia (SCN) cases developing AML as consequence of somatic CSF3R mutations ³ and, sporadically, by adaptive SGR in the context of germline GATA2 and secondary acquisition of somatic GATA2 mutation, counterbalancing the germline effect ⁴. Although SGR has been functionally demonstrated in these two above mentioned cases, given the molecular heterogeneity of myeloid neoplasia (MN) and the rarity of such genetic events, one can suspect that, in various clinical contexts, any mutation in any gene could be the SG rescuer.

During our clinical experience, we encountered a case of a 57yo. woman with newly diagnosed aplastic anemia (AA) who was found to harbor a rare germline FLT3^R311W mutation (VAF 50%; predicted to be a loss-of-function/hypomorphic alteration; Fig1) who subsequently evolved to MDS with monosomy 7. Coexisting somatic hits included non RUNT-homology domain, RUNX1^P398L mutation (VAF 19%). Ultimately, the patient progressed to AML with emergence of a FLT3^D825V (VAF 14%) and a NRAS^G13D (24%) lesions. In this case carrying GL FLT3 variant, biallelic somatic FLT3 mutation may represent maladaptive SGR. Therefore, we reviewed NGS sequencing results of 5,308 patients with MN and found three other suspected cases harboring GL variants in FLT3 gene, which inspired further investigations.

In total we identified 3 additional cases (total of 4/5308 screened patients and among 248 somatic FLT3 mutations. Interestingly, the other case GL FLT3^A680T occurred in a patient with AA (35yo.) who subsequently progressed to MDS and AML and acquired somatic NPM1^L258fs, PTPN11 ^A72V, WT1 ^A365fs and most importantly, a somatic CSF3R^L619S . The latter may represent an illustrative case of SGR, in analogy to AML developing in the context of SCN. In addition, 2 other cases with MDS or MDS/MPN were identified both presenting with cytopenia. A 53yo. woman diagnosed with MDS/MPN and GL FLT3^L262F (gnomAD: 0.00000399) with a compound heterozygous somatic JAK2^V617F mutation, again possibly serving as maladaptive clonal SGR event. Finally, we have identified a GL FLT3A291P mutation (VAF 60%, gnomAD frequency: 1.59×10-5) in a 58yo. man who eventually developed AML.

In sum, similar to other phosphotyrosine receptor kinases (PTRKs) such as CSF3R, somatic FLT3 mutations may in rare biallelic cases correspond to SGR events of hypomorphic GL mutation or alternatively but not exclusively somatic mutations in other PTRK could evolve to reveal the GL FLT3 deficiency. Indeed, in another abstract by our group (Abstract#187151) we show that somatic FLT3 mutations can accompany GL variants in CSF3R, CSF2RB, and CSF1R.

References

1 Revy P, Kannengiesser C, Fischer A. Somatic genetic rescue in Mendelian haematopoietic diseases. Nat Rev Genet. 2019 Oct;20(10):582-598.

2 Kennedy AL, Shimamura A. Genetic predisposition to MDS: clinical features and clonal evolution. Blood. 2019 Mar 7;133(10):1071-1085.

3 Germeshausen M, Kratz CP, Ballmaier M, Welte K. RAS and CSF3R mutations in severe congenital neutropenia. Blood. 2009 Oct 15;114(16):3504-5.

4 Catto LFB, Borges G, Pinto AL, Clé DV, Chahud F, Santana BA, Donaires FS, Calado RT. Somatic genetic rescue in hematopoietic cells in GATA2 deficiency.