A specific stem cell program and CD112 immunological axis dysfunctions underpinning monosomy 7-associated myeloid neoplasms.

Monosomy 7 (-7) is occurring as isolated change or in complex karyotypes in 10-20% of myeloid neoplasms with poor prognosis. Although several genes mapping at chromosome 7 have been involved in pathogenetic mechanisms, the -7 molecular landscape is not fully elucidated. Using an epi-transcriptomic approach, new biological insights emerged in monosomy 7. A private 49 stemness gene program was first identified and it included 59.2% of the targets of the homeobox transcription factors, specifically deregulated in -7 by hypermethylated intergenic enhancers. Additionally, 20.4% of the stemness program was determined by the signature generated by IKZF1/7p12.2 deficiency, responsible for upregulation of the CD112 immuno-checkpoint gene. Focusing on CD112, immunohistochemistry typically assigned its expression to bone marrow blasts and myeloid progenitors in monosomy 7. Concomitant increased expression of the inhibitory TIGIT and PVRIG receptors, and decreased expression of the activating DNAM1 receptor, significantly emerged in CD3+, and natural killer (NK) cells from patients with -7. Moreover, receptors deregulation was shown to be induced by CD34+ leukemic cells with CD112 overexpression. Development of an "ex vivo" model, that used cytotoxicity assays with primary cells from AML cases and autologous NK cells after blockade of the TIGIT and PVRIG receptors, allowed us to show enhanced cytolytic activity of NK against leukemic cells with -7. Altogether, these results first disclosed a dysfunctional TIGIT-PVRIG-DNAM1/CD112 axis in myeloid neoplasms with monosomy 7, inspiring the use of inhibitory receptors blockade to exploit the NK autologous reactivity against a still undruggable cytogenetic change of myeloid neoplasms with dismal prognosis.