B-cell acute lymphoblastic leukemia in patients with germline RUNX1 mutations

Abstract

Germline RUNX1 mutations underlie a syndrome, RUNX1-familial platelet disorder (RUNX1-FPD), characterized by bleeding symptoms that result from quantitative and/or qualitative defect in platelets and a significantly increased risk for developing hematologic malignancies. Myeloid neoplasms are the most commonly diagnosed hematologic malignancies, followed by lymphoid malignancies of T-cell origin. Here, we describe the first 2 cases of B-cell acute lymphoblastic leukemia (B-ALL) in patients with confirmed germline RUNX1 mutations. While 1 of the patients had a known diagnosis of RUNX1-FPD with a RUNX1 p.P240Hfs mutation, the other was the index patient of a kindred with a novel RUNX1 variant, RUNX1 c.587C>T (p.T196I), noted on a targeted genetic testing of the B-ALL diagnostic sample. We discuss the clinical course, treatment approaches, and the outcome for the 2 patients. Additionally, we describe transient resolution of the mild thrombocytopenia and bleeding symptoms during therapy, as well as the finding of clonal hematopoiesis with a TET2 mutant clone in 1 of the patients. It is critical to consider testing for germline RUNX1 mutations in patients presenting with B-ALL who have a personal or family history of thrombocytopenia, bleeding symptoms, or RUNX1 variants identified on genetic testing at diagnosis.

Figure 1.

Schematic representation of RUNX1 showing the germline genetic variants in RUNX1-FPD associated with lymphoid malignancies. Shown are RUNX1 single-nucleotide variants and a deletion (del) reported in this study and reported by Brown et al, associated with lymphoid malignancies, annotated to RUNX1C; NM_001754; Ensembl: ENST00000300305. aa, amino acids; ALL, NOS, acute lymphoblastic leukemia, not otherwise specified; CLL, chronic lymphocytic leukemia; NHL, non-Hodgkin lymphoma; T-ALL, T-cell acute lymphoblastic leukemia; T-LL, T lymphoblastic lymphoma; T-NHL, T-cell non-Hodgkin lymphoma; NRDB, negative regulatory domain for DNA binding; TAD, transcriptional activation domain; TID, transcriptional inhibitory domain.