P2RY8-CRLF2Fusion-Positive Acute Myeloid Leukemia With Myelodysplasia-Related Changes: Response to Novel Therapy.
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ABSTRACT:
SUBMITTER: Aypar U
PROVIDER: S-EPMC7213523 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) includes heterogeneous conditions such as previous history and specific cytogenetic and morphological properties. In this study, we analyze genetic aberrations using an RNA-based next-generation sequencing (NGS) panel assay in 45 patients with AML-MRC and detect 4 gene fusions of KMT2A-SEPT9, KMT2A-ELL, NUP98-NSD1, and RUNX1-USP42 and 81 somatic mutations. Overall, all patients had genetic aberrations comprising of not only cytogenetic changes, but also gene fusions and mutations. We also demonstrated several characteristic genetic mutations according to the AML-MRC subgroup. TP53 was the most commonly mutated gene (n = 11, 24%) and all were found in the AML-MRC subgroup with myelodysplastic syndrome-defining cytogenetic abnormalities (AML-MRC-C) (p = 0.002). These patients showed extremely poor overall survival not only in AML-MRC, but also within the AML-MRC-C subgroup. The ASXL1 (n = 9, 20%) and SRSF2 (n = 7, 16%) mutations were associated with the AML-MRC subgroup with >50% dysplasia in at least two lineages (AML-MRC-M) and were frequently co-mutated (55%, 6/11, p < 0.001). Both mutations could be used as surrogate markers to diagnose AML-MRC, especially when the assessment of multilineage dysplasia was difficult. IDH1/IDH2 (n = 13, 29%) were most commonly mutated in AML-MRC, followed by CEBPA (n = 5, 11%), PTPN11 (n = 5, 11%), FLT3 (n = 4, 9%), IDH1 (n = 4, 9%), and RUNX1 (n = 4, 9%). These mutations were not limited in any AML-MRC subgroup and could have more significance as a risk factor or susceptibility marker for target therapy in not only AML-MRC, but also other AML categories.
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Project description:Acute myeloid leukemia (AML) is a clonal myeloid neoplasm that typically arises de novo; however, some cases evolve from a preleukemic state, such as myelodysplastic syndrome (MDS). Such secondary AMLs and those with typical MDS-related clinical features are known as AMLs with myelodysplasia-related changes (AML-MRC). Because patients with AML-MRC have poor prognosis, more accurate diagnostic approaches are required. In this study, we performed targeted sequencing of 54 genes in 3 cell populations (granulocyte, blast, and T-cell fractions) using samples from 13 patients with MDS, 16 patients with clinically diagnosed AML-MRC, 4 patients with suspected AML-MRC but clinically diagnosed as AML not otherwise specified (AML-NOS), and 11 patients with de novo AML. We found that overlapping mutations, defined as those shared at least by the blast and granulocyte fractions, were significantly enriched in patients with MDS and AML-MRC, including those with suspected AML-MRC, indicating a substantial history of clonal hematopoiesis. In contrast, blast-specific nonoverlapping mutations were significantly enriched in patients with de novo AML. Furthermore, the presence of overlapping mutations, excluding DNMT3A, TET2, and ASXL1, effectively segregated patients with MDS and AML-MRC or suspected AML-MRC from patients with de novo AML. Additionally, the presence of ?3 mutations in the blast fraction was useful for distinguishing patients with AML-MRC from those with MDS. In conclusion, our approach is useful for classifying clinically diagnosable AML-MRC and identifying clinically diagnosed AML-NOS as latent AML-MRC. Additional prospective studies are needed to confirm the utility of this approach.
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Project description:A rare but clinically important diagnostic dilemma arises when cases meet the criteria for both acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) and mixed phenotype acute leukemia, especially those that evolve from myelodysplastic syndrome. We describe a 56-year-old male patient who presented with cytopenias and was initially diagnosed with myelodysplastic syndrome with single lineage dysplasia. Nearly 1 year later, this patient progressed to acute leukemia, and his blast cells simultaneously expressed T-lymphoid and myeloid antigens. Cytogenetic analysis showed a 20q deletion, and next-generation sequencing showed mutations of ASXL1, NRAS, PHF6, RUNX1, TP53, and PIGA. He was diagnosed with AML-MRC with blasts of the mixed T/myeloid phenotype according to the latest World Health Organization guidelines. In accordance with the treatment principles of AML-MRC, we chose an AML-like regimen for four cycles, but the patient did not achieve remission. Finally, we adhered to the treatment principles of mixed phenotype acute leukemia, and he achieved remission after a course of ALL-like regimen chemotherapy.
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Project description:Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) are poor outcome leukemias. Its diagnosis is based on clinical, cytogenetic, and cytomorphologic criteria, last criterion being sometimes difficult to assess. A high frequency of ASXL1 mutations have been described in this leukemia. We sequenced ASXL1 gene mutations in 61 patients with AML-MRC and 46 controls with acute myeloid leukemia without other specifications (AML-NOS) to identify clinical, cytomorphologic, and cytogenetic characteristics associated with ASXL1 mutational status. Mutated ASXL1 (ASXL1+) was observed in 31% of patients with AML-MRC compared to 4.3% in AML-NOS. Its presence in AML-MRC was associated with older age, a previous history of myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN), leukocytosis, presence of micromegakaryocytes in bone marrow, lower number of blasts in bone marrow, myelomonocytic/monocytic morphological features and normal karyotype. ASXL1 mutation was not observed in patients with myelodysplastic syndrome-related cytogenetic abnormalities or TP53 mutations. Differences in terms of overall survival were found only in AML-MRC patients without prior MDS or MDS/MPN and with intermediate-risk karyotype, having ASXL1+ patients a worst outcome than ASXL1-. We conclude that the ASXL1 mutation frequency is high in AML-MRC patients being its presence associated with specific characteristics including morphological signs of dysplasia. This association raises the possible role of ASXL1 as a surrogate marker in AML-MRC, which could facilitate the diagnosis of patients within this group when the karyotype is normal, and especially when the assessment of multilineage dysplasia morphologically is difficult. This mutation could be used as a worst outcome marker in de novo AML-MRC with intermediate-risk karyotype.
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Project description:Background/aimPrediction of response to azacitidine (AZA) treatment is an important challenge in hematooncology. In addition to protein coding genes (PCGs), AZA efficiency is influenced by various noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs), circular RNAs (circRNAs), and transposable elements (TEs).Materials and methodsRNA sequencing was performed in patients with myelodysplastic syndromes or acute myeloid leukemia before AZA treatment to assess contribution of ncRNAs to AZA mechanisms and propose novel disease prediction biomarkers.ResultsOur analyses showed that lncRNAs had the strongest predictive potential. The combined set of the best predictors included 14 lncRNAs, and only four PCGs, one circRNA, and no TEs. Epigenetic regulation and recombinational repair were suggested as crucial for AZA response, and network modeling defined three deregulated lncRNAs (CTC-482H14.5, RP11-419K12.2, and RP11-736I24.4) associated with these processes.ConclusionThe expression of various ncRNAs can influence the effect of AZA and new ncRNA-based predictive biomarkers can be defined.
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Project description:Therapy-related myelodysplasia or acute myeloid leukemia (t-MDS/AML) is a major complication of cancer treatment. We compared gene expression in CD34+ cells from patients who developed t-MDS/AML after autologous hematopoietic cell transplantation (aHCT) for lymphoma with controls who did not develop t-MDS/AML. We observed altered gene expression related to mitochondrial function, metabolism, and hematopoietic regulation in pre-aHCT samples from patients who subsequently developed t-MDS/AML. Progression to overt t-MDS/AML was associated with additional alterations in cell-cycle regulatory genes. An optimal 38-gene PBSC classifier accurately distinguished patients who did or did not develop t-MDS/AML in an independent group of patients. We conclude that genetic programs associated with t-MDS/AML are perturbed long before disease onset, and accurately identify patients at risk for this complication.
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Project description:Children with P2RY8-CRLF2-positive acute lymphoblastic leukemia have an increased relapse risk. Their mutational and transcriptional landscape, as well as the respective patterns at relapse remain largely elusive. We, therefore, performed an integrated analysis of whole-exome and RNA sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway-activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RY8-CRLF2 that was lost in 32% of relapses, all other genomic alterations affecting lymphoid development (58%) and cell cycle (39%) remained stable. Only IKZF1 alterations predominated in relapsing cases (P=0.001) and increased from initially 36 to 58% in matched cases. IKZF1's critical role is further corroborated by its specific transcriptional signature comprising stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance. Our findings support the notion that P2RY8-CRLF2 is dispensable for relapse development and instead highlight the prominent rank of IKZF1 for relapse development by mediating self-renewal and homing to the bone marrow niche. Consequently, reverting aberrant IKAROS signaling or its disparate programs emerges as an attractive potential treatment option in these leukemias.
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Project description:MYC is an oncoprotein that coordinates the expression of genes involved in metabolism, cell differentiation and survival in various types of malignancies. However, the underlying oncogenic mechanisms and the clinical significance of MYC expression in the acute myeloid leukemia with myelodysplasia related changes (AML-MRC) remain to be answered. A total of 135 patients were retrospectively identified using Total Cancer Care (TCC) Moffitt Cancer Center (MCC) databases. Diagnosis of AML-MRC was based on the 2016 WHO classification utilizing bone marrow (BM) evaluation. MYC protein expression level was assessed by immunohistochemistry (IHC) staining using paraffin-embedded BM trephine biopsy samples obtained at the time of diagnosis or relapse. Concurrent somatic mutations were assessed using targeted next generation sequencing that include 54 genes. A total of 38% (n?=?51) and 62% (n?=?84) patients had high and low MYC expression, respectively. The most common somatic mutation in our cohort was TP53 followed by DNMT3A, and ASXL1. The median OS was significantly longer in low MYC patients (median OS 42.3 vs. 17.05 months, p?=?0.0109). Multivariate analysis including MYC expression level, transplantation status, gender and age demonstrated high MYC expression (HR 1.77, 95% CI 1.004-3.104, p?=?0.045) to be an independent poor prognostic factor. Further studies are needed to identify the underlying mechanism of MYC driven oncogenesis in AML-MRC. Additionally, the prognostic impact of MYC on the AML survival in a larger cohort that include diverse somatic mutations and chromosomal abnormalities requires further investigation.
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