Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality

Abstract

Monosomy of chromosome 7 is the most frequent autosomal monosomy in acute myeloid leukemia (AML), where it associates with poor clinical outcomes. However, molecular features associated with this sole monosomy subtype (-7 AML) which may give insights into the basis for its poor prognosis have not been characterized. In this study, we analyzed 36 cases of -7 AML for mutations in 81 leukemia/cancer-associated genes using a customized targeted next-generation sequencing panel (Miseq). Global gene and microRNA expression profiles were also determined using paired RNA and small RNA sequencing data. Notably, gene mutations were detected in all the major AML-associated functional groups, which include activated signaling, chromatin remodeling, cohesin complex, methylation, NPM1, spliceosome, transcription factors and tumor suppressors. Gene mutations in the activated signaling and chromatin remodeling groups were relatively more frequent in patients <60 years of age, who also had more mutations in the methylation and spliceosome groups compared to patients {greater than or equal to} 60 years of age. Novel recurrent mutational events in AML were identified in the SMARCA2 gene. In patients {greater than or equal to} 60 years of age, the presence of spliceosome mutations associated with a lower complete remission rate (p=0.03). RNA sequencing revealed distinct gene and microRNA expression patterns between the sole -7 and non-7 AML cases, with reduced expression as expected of many genes and microRNAs mapped to chromosome 7, and overexpression of ID1, MECOM, and PTPRM, among others. Overall, our findings illuminate a number of molecular features of the underlying aggressive pathobiology in -7 AML patients.

The impact of concomitant cytogenetic abnormalities on acute myeloid leukemia with monosomy 7 or deletion 7q after HLA‐matched allogeneic stem cell transplantation

“…The 2-year cumulative incidence of relapse was 36.7% for the "-7/7q-± CK group," 47.8% for the "MK group," 51% for the "-5/5qgroup," 62.9% and 68.4% for the "inv(3) group" (P < .001, Figure 2A), which translated into a 2-year probability of LFS of 48%, 36.4%, 28.4%, 19.1% and 17.3% for the "-7/7q-± CK," "MK," "-5/5q-," "abn(17p)" and "inv(3)" groups, respectively (P < .001, Figure 2C). The 2-year NRM was similar across our five cytogenetic <.0001 20 (16)(17)(18)(19)(20)(21)(22)(23)(24) .99 23 (18)(19)(20)(21)(22)(23)(24)(25)(26)(27) <.0001 27 (22)(23)(24)(25)(26)(27)(28)(29)(30)(31) <.0001 13 (10)(11)(12)(13)(14)(15)(16) <.0001 26 (22)(23)(24)(25)(26)(27)(28)(29)…”

“…The most frequent autosomal monosomy reported in AML is -7/7q-, 22,23 and is consistently associated with a very bad prognosis after chemotherapy alone. 3,24 As other high-risk AML, SCT appears as the best consolidation strategy with prolonged disease-free survival in about 40% of the patients.…”

“…15 20 (12-28) . 32 (29)(30)(31)(32)(33)(34)(35) 7q-vs -7 7q-44 (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49) .005 21 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26) .72 35 (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41) .004 42 (36)(37)(38)(39)(40)(41)(42)(43)(44)(45)…”

Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery

“…Isolated trisomy 13 is associated with RUNX1, ASXL1, BCOR, and spliceosome-complex mutations, upregulated FOXO1 and FLT3 expression, and downregulated SPRY expression. 21 This evidence suggests that leukemia-specific and aneuploidy-related mechanisms may cooperate in the selection of evolved clones able to overcome the unfitness barrier of aneuploidy. 18 CUX1 is a haploinsufficient tumor suppressor in -7/del(7q) cases, 19,20 and monosomy 7 AML displays elevated ID1, MECOM, and PTPRM.…”

“…18 CUX1 is a haploinsufficient tumor suppressor in -7/del(7q) cases, 19,20 and monosomy 7 AML displays elevated ID1, MECOM, and PTPRM. 21 This evidence suggests that leukemia-specific and aneuploidy-related mechanisms may cooperate in the selection of evolved clones able to overcome the unfitness barrier of aneuploidy.…”