Clonal interference of signaling mutations worsens prognosis in core-binding factor acute myeloid leukemia

Mutations in receptor tyrosine kinase/RAS signaling pathway genes are frequent in core-binding factor (CBF) acute myeloid leukemias (AMLs), but their prognostic relevance is debated. A subset of CBF AML patients harbors several signaling gene mutations. Genotyping of colonies and of relapse samples indicates that these arise in independent clones, thus defining a process of clonal interference (or parallel evolution). Clonal interference is pervasive in cancers, but the mechanisms underlying this process remain unclear, and its prognostic impact remains unknown. We analyzed a cohort of 445 adult and pediatric patients with CBF AML treated with intensive chemotherapy and with deep sequencing of 6 signaling genes (, , , , , ). A total of 152 (34%), 167 (38%), and 126 (28%) patients harbored no, a single, and multiple signaling clones (clonal interference), respectively. Clonal interference of signaling mutations was associated with older age ( = .004) and inv(16) subtype ( = .025) but not with white blood cell count or mutations in chromatin or cohesin genes. The median allele frequency of signaling mutations was 31% in patients with a single clone or clonal interference ( = .14). The repertoire of , , and / variants differed between groups. Clonal interference did not affect complete remission rate or minimal residual disease after 1-2 courses, but it did convey inferior event-free survival ( < 10), whereas the presence of a single signaling clone did not ( = .44). This inferior outcome was independent of clinical parameters and of the presence of specific signaling clones. Our results suggest that specific clonal architectures can herald distinct prognoses in AML

Differential effects on gene transcription and hematopoietic differentiation correlate with GATA2 mutant disease phenotypes

Heterozygous GATA2 mutations underlie an array of complex hematopoietic and lymphatic diseases. Analysis of the literature reporting three recurrent GATA2 germline (g) mutations (gT354M, gR396Q and gR398W) revealed different phenotype tendencies. Although all three mutants differentially predispose to myeloid malignancies, there was no difference in leukemia-free survival for GATA2 patients. Despite intense interest, the molecular pathogenesis of GATA2 mutation is poorly understood. We functionally characterized a GATA2 mutant allelic series representing major disease phenotypes caused by germline and somatic (s) mutations in zinc finger 2 (ZF2). All GATA2 mutants, except for sL359V, displayed reduced DNA-binding affinity and transactivation compared with wild type (WT), which could be attributed to mutations of arginines critical for DNA binding or amino acids required for ZF2 domain structural integrity. Two GATA2 mutants (gT354M and gC373R) bound the key hematopoietic differentiation factor PU.1 more strongly than WT potentially perturbing differentiation via sequestration of PU.1. Unlike WT, all mutants failed to suppress colony formation and some mutants skewed cell fate to granulocytes, consistent with the monocytopenia phenotype seen in GATA2-related immunodeficiency disorders. These findings implicate perturbations of GATA2 function shaping the course of development of myeloid malignancy subtypes and strengthen complete or nearly complete haploinsufficiency for predisposition to lymphedema.C-E Chong, P Venugopal, PH Stokes, YK Lee, PJ Brautigan, DTO Yeung, M Babic, GA Engler, SW Lane, M Klingler-Hoffmann, JM Matthews, RJ D'Andrea, AL Brown, CN Hahn, and HS Scot

Outcomes and mutational analysis of patients with lower-risk non-del5q myelodysplastic syndrome treated with antithymocyte globulin with or without ciclosporine A

International audienceImmunosuppressive treatment is a disease-modifying therapy for lower-risk myelodysplastic syndromes (MDS). However, IST is relatively rarely used and long-term outcomes of patients are seldom reported. We retrospectively studied outcomes of 20 patients with lower-risk non del 5q MDS with transfusion dependency, with horse or rabbit antithymocyte globulin ± ciclosporine A, and frontline eltrombopag in two of them. IPSS-R was low, intermediate and high in 30%, 55% and 10% of the patients, respectively. Fifty-five percent of the patients had hypocellular bone marrow (BM). Baseline mutations were detected in 31.5% of the patients and were more frequent in patients with normo/hypercellular MDS than in patients with hypocellular MDS. Transfusion independence rate for both red blood cells (RBC) and platelets was achieved in 45% of patients. RBC transfusion duration ≤6 months, B-cell counts >0.2 G/L and, marginally, BM blasts ≤2% were associated with higher transfusion independence rate. Age and cellularity did not influence the response rate. Median transfusion independence duration was 53 months. Cumulative incidence of progression to a more aggressive myeloid disease was 0 in patients without baseline mutations and 33% in patients with baseline mutations (P = .008). Median progression-free and overall survival after treatment onset and median overall survival after loss of transfusion independence were 45.5 months, 68 months and not reached, respectively. In conclusion, antithymocyte globulin ± ciclosporine A results in durable responses in MDS, irrespective of age, in patients with lower-risk disease without B-cell lymphopenia and treated early in the course of the disease

Outcomes and mutational analysis of patients with lower-risk non-del5q myelodysplastic syndrome treated with antithymocyte globulin with or without ciclosporine A

International audienceImmunosuppressive treatment is a disease-modifying therapy for lower-risk myelodysplastic syndromes (MDS). However, IST is relatively rarely used and long-term outcomes of patients are seldom reported. We retrospectively studied outcomes of 20 patients with lower-risk non del 5q MDS with transfusion dependency, with horse or rabbit antithymocyte globulin ± ciclosporine A, and frontline eltrombopag in two of them. IPSS-R was low, intermediate and high in 30%, 55% and 10% of the patients, respectively. Fifty-five percent of the patients had hypocellular bone marrow (BM). Baseline mutations were detected in 31.5% of the patients and were more frequent in patients with normo/hypercellular MDS than in patients with hypocellular MDS. Transfusion independence rate for both red blood cells (RBC) and platelets was achieved in 45% of patients. RBC transfusion duration ≤6 months, B-cell counts >0.2 G/L and, marginally, BM blasts ≤2% were associated with higher transfusion independence rate. Age and cellularity did not influence the response rate. Median transfusion independence duration was 53 months. Cumulative incidence of progression to a more aggressive myeloid disease was 0 in patients without baseline mutations and 33% in patients with baseline mutations (P = .008). Median progression-free and overall survival after treatment onset and median overall survival after loss of transfusion independence were 45.5 months, 68 months and not reached, respectively. In conclusion, antithymocyte globulin ± ciclosporine A results in durable responses in MDS, irrespective of age, in patients with lower-risk disease without B-cell lymphopenia and treated early in the course of the disease