The mutational burden of therapy-related myeloid neoplasms is similar to primary myelodysplastic syndrome but has a distinctive distribution

Singhal, Deepak; Wee, Li Yan A.; Kutyna, Monika M; Chhetri, Rakchha; Geoghegan, Joel; Schreiber, Andreas W.; Jiang, Feng; Wang, Paul P. S.; Babic, Milena; Parker, Wendy T; Hiwase, Smita; Edwards, Suzanne; Moore, Sarah; Branford, Susan; Kuzmanovic, Teodora; Singhal, Nimit; Gowda, Raghu; Brown, Anna L.; Arts, Peer; To, Luen Bik; Bardy, Peter; Lewis, Ian D.; D’Andrea, Richard J.; Maciejewski, Jaroslaw P.; Scott, Hamish S.; Hahn, Christopher N.; Hiwase, Devendra

doi:10.1038/s41375-019-0479-8

Cited by 45 publications

(56 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…51,52,[62][63][64] Mechanistically, acquisition of secondary pathogenic somatic mutations may be the result of increased mutagenic processes in germline RUNX1 carriers, 63,65 characterized as early-onset clonal hematopoiesis, and potentially a result of dysregulated DNA repair pathways associated with RUNX1 mutation. 66 Reflecting the diverse germline phenotypic manifestations, RUNX1 is also somatically mutated across a spectrum of sporadic HM subtypes, including MDS/AML (10%), 58,59 chronic myeloid leukemia blast crisis (40%), 67 therapy-related myeloid neoplasm (16%), 68,69 T-cell acute lymphoblastic leukemia (18%) 70 and HM transformation in patients with severe congenital neutropenia (64%) 71 or Fanconi anemia (20%). 72 Interestingly, the spectrum of somatic mutation types mirrors that seen in germline predisposition, making deconvolution of germline vs somatic mutations in a patient, being screened at malignancy presentation, complex.…”

Section: Spectrum Of Runx1 Germline Mutationsmentioning

confidence: 99%

Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

Brown

Hahn

Scott

2020

Blood

Self Cite

View full text Add to dashboard Cite

Abstract Recognition that germline mutations can predispose individuals to blood cancers, often presenting as secondary leukemias, has largely been driven in the last 20 years by studies of families with inherited mutations in the myeloid transcription factors (TFs) RUNX1, GATA2, and CEBPA. As a result, in 2016, classification of myeloid neoplasms with germline predisposition for each of these and other genes was added to the World Health Organization guidelines. The incidence of germline mutation carriers in the general population or in various clinically presenting patient groups remains poorly defined for reasons including that somatic mutations in these genes are common in blood cancers, and our ability to distinguish germline (inherited or de novo) and somatic mutations is often limited by the laboratory analyses. Knowledge of the regulation of these TFs and their mutant alleles, their interaction with other genes and proteins and the environment, and how these alter the clinical presentation of patients and their leukemias is also incomplete. Outstanding questions that remain for patients with these germline mutations or their treating clinicians include: What is the natural course of the disease? What other symptoms may I develop and when? Can you predict them? Can I prevent them? and What is the best treatment? The resolution of many of the remaining clinical and biological questions and effective evidence-based treatment of patients with these inherited mutations will depend on worldwide partnerships among patients, clinicians, diagnosticians, and researchers to aggregate sufficient longitudinal clinical and laboratory data and integrate these data with model systems.

show abstract

Section: Spectrum Of Runx1 Germline Mutationsmentioning

confidence: 99%

Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

Brown

Hahn

Scott

2020

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…Seventeen percent of these t-AML patients displayed IDH1/IDH2 mutations [ 63 ]. The distribution of IDH1/IDH2 mutations was highly variable among these three subgroups: 33% of IDH -mutant among secondary-type t-AMLs; 8.5% of IDH-mutant among TP53 -mutated t-AMLs; 10% of IDH -mutant among de novo /pan-AML t-AML [ 79 ]. T-AMLs with secondary-type mutations displayed an older age and had more recurrent driver mutations than t-AML with de novo /pan-AML mutations [ 63 ].…”

Section: Idh Mutations In Therapy-related Aml and Mdsmentioning

confidence: 99%

Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes and in Acute Myeloid Leukemias

Testa

Castelli

2020

Cancers

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is a heterogeneous disease generated by the acquisition of multiple genetic and epigenetic aberrations which impair the proliferation and differentiation of hematopoietic progenitors and precursors. In the last years, there has been a dramatic improvement in the understanding of the molecular alterations driving cellular signaling and biochemical changes determining the survival advantage, stimulation of proliferation, and impairment of cellular differentiation of leukemic cells. These molecular alterations influence clinical outcomes and provide potential targets for drug development. Among these alterations, an important role is played by two mutant enzymes of the citric acid cycle, isocitrate dehydrogenase (IDH), IDH1 and IDH2, occurring in about 20% of AMLs, which leads to the production of an oncogenic metabolite R-2-hydroxy-glutarate (R-2-HG); this causes a DNA hypermethylation and an inhibition of hematopoietic stem cell differentiation. IDH mutations differentially affect prognosis of AML patients following the location of the mutation and other co-occurring genomic abnormalities. Recently, the development of novel therapies based on the specific targeting of mutant IDH may contribute to new effective treatments of these patients. In this review, we will provide a detailed analysis of the biological, clinical, and therapeutic implications of IDH mutations.

show abstract

“…Patients #9 and #11 were AZA responders (respectively, mCR and SD with HI), whereas patients #14, #15, and #19 were in progression. Median number of AZA cycles was 5 (range, [3][4][5][6][7][8], and median OS was 14 months (range, [3][4][5][6][7][8][9][10][11][12][13][14][15]. In patients #9, #14, and #15, we failed to detect any change of mutated clone VAF under AZA treatment.…”

Section: Correlation Between Aza Response and Putative Function Of mentioning

confidence: 77%

“…Emergence of clones with mutation in transcription factor under AZA treatment occurred in five patients (#5, #7, #10, #16, and #17; Figure S1). Median number of cycles was 4 (range 1-10), and median OS was 15 months (range [6][7][8][9][10][11][12][13][14][15]. Appearance of these mutations occurred during stable disease in patients #7 and #16 and at the time of progression in patients #5, #7, and #17.…”

Section: Correlation Between Aza Response and Putative Function Of mentioning

confidence: 99%

See 1 more Smart Citation

Clonal selection in therapy‐related myelodysplastic syndromes and acute myeloid leukemia under azacitidine treatment

Calleja

Yun

Moreilhon

et al. 2020

European J of Haematology

View full text Add to dashboard Cite

Introduction Therapy‐related myelodysplastic syndrome and acute myeloid leukemia (t‐MDS/AML) are defined as complications of previous cytotoxic therapy. Azacitidine (AZA), a hypomethylating agent, has showed activity in t‐MDS/AML. Objectives We evaluated the clonal dynamics of AZA‐treated t‐MDS/AML. Methods We collected bone marrow samples, at diagnosis and during treatment, from AZA‐treated t‐MDS/AML patients. NGS on 19 myeloid genes was performed, and candidate mutations with a variant allele frequency >5% were selected. Results Seven t‐AML and 12 t‐MDS were included with median age of 71 (56‐82) years old, median number of AZA cycles of 6 (1‐15), and median overall survival (OS) of 14 (3‐29) months. We observed correlation between AZA response and clonal selection. Decrease of TP53‐mutated clone was correlated with response to AZA, confirming AZA efficacy in this subgroup. In some patients, emergence of mutations was correlated with progression or relapse without impact on OS. Clones with mutations in genes for DNA methylation regulation frequently occurred with other mutations and remained stable during AZA treatment, independent of AZA response. Conclusion We confirmed that the molecular complexity of t‐MNs and that the follow‐up of clonal selection during AZA treatment could be useful to define treatment combination.

show abstract

The mutational burden of therapy-related myeloid neoplasms is similar to primary myelodysplastic syndrome but has a distinctive distribution

Cited by 45 publications

References 40 publications

Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes and in Acute Myeloid Leukemias

Clonal selection in therapy‐related myelodysplastic syndromes and acute myeloid leukemia under azacitidine treatment

Contact Info

Product

Resources

About