High frequency of germline RUNX1 mutations in patients with RUNX1-mutated AML

Abstract

RUNX1 is mutated in ∼10% of adult acute myeloid leukemia (AML). Although most RUNX1 mutations in this disease are believed to be acquired, they can also be germline. Indeed, germline RUNX1 mutations result in the well-described autosomal-dominant familial platelet disorder with predisposition to hematologic malignancies (RUNX1-FPD, FPD/AML, FPDMM); ∼44% of affected individuals progress to AML or myelodysplastic syndromes. Using the Leucegene RUNX1 AML patient group, we sought to investigate the proportion of germline vs acquired RUNX1 mutations in this cohort. Our results showed that 30% of RUNX1 mutations in our AML cohort are germline. Molecular profiling revealed higher frequencies of NRAS mutations and other mutations known to activate various signaling pathways in these patients with RUNX1 germline–mutated AML. Moreover, 2 patients (mother and son) had co-occurrence of RUNX1 and CEBPA germline mutations, with variable AML disease onset at 59 and 27 years, respectively. Together, these data suggest a higher than anticipated frequency of germline RUNX1 mutations in the Leucegene cohort and further highlight the importance of testing for RUNX1 mutations in instances in which allogeneic stem cell transplantation using a related donor is envisioned.

Born to RUNX1

“…This study provides insights into the factors that influence the effective secretion of FVIII that may have implications for in vitro protein production systems and in vivo gene therapy. 1 FVIII deficiency causes the bleeding disorder hemophilia A. It has been known for decades that FVIII is a difficult protein to express both in vitro and in vivo.…”

NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021

“…36 The prognostic influence of TKD 816 and other mutations in exon 17 (mutKIT17) versus other recurrent KIT mutations in CBF-AML, such as exon 8 (mutKIT8), have been investigated. 37,38 In an analysis of adult patients aged ,60 years with CBF-AML treated with intensive chemotherapy on CALGB trials (n5110), KIT mutations (mutKIT17 and mutKIT8) among patients with inv(16) were associated with a higher cumulative incidence of relapse at 5 years (56% vs 29%; P5.05) and a decreased 5-year OS rate (48% vs 68%) compared with those with wild-type KIT; in multivariate analysis, the presence of KIT mutations remained a significant predictor of decreased OS in the subgroup with inv (16). In patients with t(8;21), KIT mutations were associated with a higher incidence of relapse at 5 years (70% vs 36%; P5.017), but no difference was observed in 5-year OS (42% vs 48%).…”

“…The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network ® (NCCN ® ) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way. 1 University of Colorado Cancer Center; 2 University of Michigan Rogel Cancer Center; 3 Abramson Cancer Center at the University of Pennsylvania; 4 Fred & Pamela Buffett Cancer Center; 5 Robert H. Lurie Comprehensive Cancer Center of Northwestern University; 6 Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; 7 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute; 8 Massachusetts General Hospital Cancer Center; 9 Mayo Clinic Cancer Center; 10 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; 11 University of Wisconsin Carbone Cancer Center; 12 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; 13 Moffitt Cancer Center; 14 Stanford Cancer Institute; 15 City of Hope National Medical Center; 16 St. Jude Children's Research Hospital/The University of Tennessee Health Science Center; 17 The Ohio State University Comprehensive Cancer Center -James Cancer Hospital and Solove Research Institute; 18 Duke Cancer Institute; 19 Fox Chase Cancer Center; 20 UCSF Helen Diller Family Comprehensive Cancer Center; 21 Yale Cancer Center/Smilow Cancer Hospital; 22 Roswell Park Comprehensive Cancer Center; 23 UCLA Jonsson Comprehensive Cancer Center; 24 The University of Texas MD Anderson Cancer Center; 25 Huntsman Cancer Institute at the University of Utah; 26 Dana-Farber/ Brigham and Women's Cancer Center; 27 Vanderbilt-Ingram Cancer Center;…”

“…Relative to sporadic cases of AML and MDS, the prevalence of known familial acute leukemia and MDS is considered rare; but with increasing recognition of germline mutations associated with predisposition to developing AML/MDS, identifying these syndromes is important for optimal management of patients and their relatives. [13][14][15][16] Evaluation for an underlying familial syndrome in a patient with acute leukemia or MDS should involve a screening history, focused physical examination, and diagnostic genetic testing. 13,17 In particular, the screening evaluation should determine whether the patient has a family history of hematologic malignancies (including AML, acute lymphoblastic leukemia [ALL], or aplastic leukemia) or unexplained leukopenia, anemia (eg, aplastic anemia, macrocytic anemia), and/or thrombocytopenia within 2 generations.…”

Restoring RUNX1 deficiency in RUNX1 familial platelet disorder by inhibiting its degradation

“…3 RUNX1 is mutated in ;10% of cases of adult AML, 30% of which are germline mutations. 4,5 RUNX1-FPD mutations generate null, hypomorphic, or dominant-negative alleles. 2,[6][7][8] At conception, patients with RUNX1-FPD possess 1 wild-type allele, producing normal protein, albeit at approximately half-normal levels.…”