Kiran Tawana

Disease evolution and outcomes in familial AML with germline CEBPA mutations.

In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.

GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations.

GATA2 mutations have recently been reported in acute myeloid leukaemia (AML) patients with CEBPA‐double mutations. To explore their impact on this favourable‐risk disease, we determined GATA2 status in 153 sporadic AML patients and three members of a germ‐line CEBPA‐mutant family at AML presentation. Overall, 27% (15/55) CEBPA‐double, 16% (7/43) CEBPA‐single and 0% (0/55) normal karyotype/CEBPA‐wild‐type patients were GATA2‐mutant. All familial AML patients acquired both a second CEBPA and a GATA2 mutation. CEBPA and GATA2 mutant levels indicated that both mutations were likely to be early events in leukaemogenesis. GATA2 status did not impact on the favourable outcome of CEBPA‐double/FLT3‐inernal tandem duplication‐negative patients.

Highly variable clinical manifestations in a large family with a novel GATA2 mutation

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Inherited DDX41 mutations: 11 genes and counting.

In this issue of Blood , [Lewinsohn and colleagues][1] report on the inherited predisposition to hematologic malignancies (HMs) in 9 pedigrees with germ line mutations in the DEAD/H-box RNA helicase gene, DDX41 .[1][2] ![Figure][3] The genetic landscape of inherited HM. The order of the 11

Clinical utility gene card for: Familial platelet disorder with associated myeloid malignancies

Clinical utility gene card for: Familial platelet disorder with associated myeloid malignancies

GATA2 monoallelic expression underlies reduced penetrance in inherited GATA2-mutated MDS/AML.

Saudi Arabian Ministry of Higher Education through a doctoral scholarship awarded to A.F.A.S. and a Bloodwise Programme grant (14032) awarded to J.F., T.V., and I.D.

Recurrent somatic JAK-STAT pathway variants within a RUNX1-mutated pedigree

Germline variants within the transcription factor RUNX1 are associated with familial platelet disorder and acute leukemia in over 40% of carriers. At present, the somatic events triggering leukemic transformation appear heterogeneous and profiles of leukemia initiation across family members are poorly defined. We report a new RUNX1 family where three sisters harboring a germline nonsense RUNX1 variant, c.601C>T (p.(Arg201*)), developed acute myelomonocytic leukemia (AML) at 5 years of age. Whole-exome sequencing of tumor samples revealed all three siblings independently acquired variants within the JAK-STAT pathway, specifically targeting JAK2 and SH2B3 (a negative regulator of JAK2), while also sharing the 46/1 haplotype linked with sporadic JAK2-positive myeloproliferative neoplasms. In-depth chromosomal characterization of tumors revealed acquired copy number gains and uniparental disomy amplifying RUNX1, JAK2 and SH2B3 variants, highlighting the significance of co-operation between these disrupted pathways. One sibling, presenting with myelodysplasia at 14 years, had no evidence of clonal or subclonal JAK2 or SH2B3 variants, suggesting the latter were specifically associated with leukemic transformation in her sisters. Collectively, the clinical and molecular homogeneity across these three young siblings provides the first notable example of convergent AML evolution in a RUNX1 pedigree, with the recurrent acquisition of JAK-STAT pathway variants giving rise to high-risk AML, characterized by chemotherapy resistance and relapse.