Recurrent genetic defects on chromosome 5q in myeloid neoplasms

Abstract

BackgroundDeletion of chromosome 5q (del(5q)) is the most common karyotypic abnormality in myeloid neoplasms.Materials and MethodsTo define the pathogenic molecular features associated with del(5q), next–generation sequencing was applied to 133 patients with myeloid neoplasms (MDS; N = 69, MDS/MPN; N = 5, sAML; N = 29, pAML; N = 30) with del(5q) as a sole abnormally or a part of complex karyotype and results were compared to molecular features of patients diploid for chr5.FindingsA number of 5q genes with haploinsufficient expression and/or recurrent somatic mutations were identified; for these genes, CSNK1A1 and G3BP1 within the commonly deleted 5q region and DDX41 within a commonly retained region were most commonly affected by somatic mutations. These genes showed consistent haploinsufficiency in deleted cases; low expression/mutations of G3BP1 or DDX41 were associated with poor survival, likely due to decreased cellular function. The most common mutations on other chromosomes in patients with del(5q) included TP53, and mutations of FLT3 (ITD or TKD), NPM1 or TET2 and were mutually exclusive. Serial sequencing allowed for definition of clonal architecture and dynamics, in patients with exome sequencing allelic imbalance for informative SNPs facilitated simultaneous approximation of clonal size of del(5q) and clonal burden for somatic mutations.InterpretationOur results illuminate the spectrum of molecular defects characteristic of del(5q), their clinical impact and succession of stepwise evolution.

Myeloid neoplasms with germline DDX41 mutation

“…The molecule was originally associated with its responsiveness against MDS patients with a chromosomal aberration of −5q [63], where 50% of patients showed cytogenetic remission [64]. DDX41 does not lie within the commonly deleted region of 5q [65]; however, recently it was shown that MDS patients with DDX41 mutations or low gene expression respond better to treatment with lenalidomide than MDS patients without DDX41 alteration [19]. The mechanism of this benefit is currently unknown.…”

Molecular pathogenesis of myelodysplastic syndromes with deletion 5q

“…The genes HSPA9 (Mitochondrial 70 kDa heat shock protein (mtHsp70), also known as mortalin) and CD74 are encoded within or near the proximal CDR at chromosome 5q31.2 and 5q32; respectively, with corresponding expression levels consistent with allelic insufficiency in del(5q) MDS . In an HSPA9 murine knockdown model, erythroid precursors, B lymphocytes, and MEP were significantly reduced .…”

“…The genes HSPA9 (Mitochondrial 70 kDa heat shock protein (mtHsp70), also known as mortalin) and CD74 are encoded within or near the proximal CDR at chromosome 5q31.2 and 5q32; respectively, with corresponding expression levels consistent with allelic insufficiency in del(5q) MDS. 30 In an HSPA9 murine knockdown model, erythroid precursors, B lymphocytes, and MEP were significantly reduced. 31 Another study showed that a heterozygous, single mutant murine model of HSPA9 and HLA class II histocompatibility antigen gamma or invariant chain gene, CD74, displayed reduced bone marrow-derived colony-forming unit-preB (CFU-preB) compared to the wild type, suggesting that heterozygous loss of CD74 and HSPA9 cooperated to induce similar B cell phenotypes that occur in MDS patients with del(5q), although the precise underlying mechanism has not been elucidated.…”

Genomic profiling of acute myeloid leukaemia associated with ataxia telangiectasia identifies a complex karyotype with wild‐type TP53 and mutant KRAS, G3BP1 and IL7R

“…The stop‐gain substitution c.1275T>A (p.Leu377*), causing premature truncation within the RNA recognition and binding domain, falls within the common AML 5q deletion (Figure 1B) and shows increasing variant allele frequency (VAF) in the tumour samples (50%, 83%, 91% and 85% in BM, T1, T2 and T5, respectively). In myeloid neoplasms with 5q deletions, G3BP1 demonstrates haploinsufficiency and is associated with poor survival 12 …”