Association Between B-Cell Marker Expression and RUNX1 Lesions in Acute Myeloid Leukemia, Beyond RUNX1::RUNX1T1 Fusion: Diagnostic Pitfalls with Mixed-Phenotype Acute Leukemia—B/Myeloid

Acute myeloid leukemia (AML) with <i>RUNX1</i>::<i>RUNX1T1</i> fusion is well known to often demonstrate aberrant upregulation of CD19 expression. We studied the clinicopathologic and genetic features of 16 cases of AML with various <i>RUNX1</i> lesions, including mutations, copy number gains, and translocations other than fusions with <i>RUNX1T1</i>. Most of these cases were classified as AML-myelodysplasia-related or AML-post-cytotoxic therapy based on the cytogenetic and molecular work-up. These neoplasms showed partial expression of one or more B-cell antigens by flow cytometry and/or immunohistochemistry, fulfilling the criteria for mixed-phenotype acute leukemia (MPAL)-B/myeloid (i.e., ≥20% blasts expressing B and myeloid lineage antigens) in most cases. These findings suggest that AML cases with <i>RUNX1</i> lesions including mutations, copy number gains, and translocations other than <i>RUNX1T1</i> fusion, also commonly express B-cell markers, imparting a "mixed-lineage-like" immunophenotype in cases of AML that otherwise fulfill the criteria for other defined subtypes. We present these cases as to caution regarding this potential diagnostic pitfall and favor a diagnosis of AML with <i>RUNX1</i> lesion(s) in the setting of a case of AML with myeloid/B-cell antigen expression, a history of myelodysplasia or cytotoxic therapy, the demonstration of pDC differentiation by flow cytometry (generally associated with the presence of a <i>RUNX1</i> mutation), and the presence of a <i>RUNX1</i> lesion (mutation, copy number gain, and/or translocation exclusive of a rearrangement with <i>RUNX1T1</i>).