A specific stem cell program and CD112 immunological axis dysfunctions underpinning monosomy 7-associated myeloid neoplasms
Summary
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, specif
Content
# A specific stem cell program and CD112 immunological axis dysfunctions underpinning monosomy 7-associated myeloid neoplasms
*Published: 2026 May 11*
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.
DOI: 10.1038/s41392-026-02681-w