Abstract
For most acute myeloid leukemia (AML) patients, an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of sustained remissions and long-term survival. At diagnosis, high expression of the AML-associated genes BAALC (brain and acute leukemia, cytoplasmic) and MN1 (meningioma-1) were repeatedly linked to inferior outcomes in patients consolidated with chemotherapy while data for patients receiving HSCT remain limited. Using clinically applicable digital droplet PCR assays, we analyzed the diagnostic BAALC/ABL1 and MN1/ABL1 copy numbers in 302 AML patients. High BAALC/ABL1 and MN1/ABL1 copy numbers associated with common adverse prognostic factors at diagnosis. However, while high diagnostic copy numbers of both genes associated with shorter event free survival (EFS) and overall survival (OS) in patients receiving chemotherapy, there was no prognostic impact in patients undergoing HSCT. Our data suggests that the adverse prognostic impact of high BAALC and MN1 expression are mitigated by allogeneic HSCT. But preHSCT BAALC/ABL1 and MN1/ABL1 assessed in remission prior to HSCT remained prognosticators for EFS and OS independent of the diagnostic expression status. Whether allogeneic HSCT may improve survival for AML patients with high diagnostic BAALC or MN1 expression should be investigated prospectively and may improve informed decisions towards individualized consolidation options in AML.
Highlights
Acute myeloid leukemia (AML) is a highly heterogeneous disease for which reliable risk stratifications are needed to individualize treatment strategies [1]
While BAALC maps to chromosome band 8q22.3 and was initially identified in AML patients harboring a trisomy 8 [7], MN1 is located on chromosome 22q12.3 and a transcription coactivator firstly described in meningioma pathogenesis [8]
High BAALC/ABL1 copy numbers associated with a lower frequency of nucleophosmin 1 (NPM1) mutations (P < 0.001), FLT3-ITD (P < 0.001), DNMT3A mutations (P = 0.03), by trend TET2 mutations (P = 0.10), and a higher frequency of RUNX1 mutations (P = 0.004), higher MN1/ABL1 copy numbers (P < 0.001), higher GPR56 expression (P < 0.001), and by trend higher EVI1 expression (P = 0.08) at diagnosis
Summary
Acute myeloid leukemia (AML) is a highly heterogeneous disease for which reliable risk stratifications are needed to individualize treatment strategies [1]. Potential consolidation therapies for AML patients in remission after successful induction therapy include intensive chemotherapy cycles alone or an allogeneic hematopoietic stem cell transplantation (HSCT). Through immunological graft-versus-leukemia (GvL) effects, where the donor’s immunocompetent cells are believed to eradicate residual disease [2, 3], allogeneic HSCT. The AML-associated genes BAALC (brain and acute leukemia, cytoplasmatic) and MN1 (meningioma-1) have been shown to be physiologically expressed at high levels in myeloid progenitor cells and downregulated during maturation and to promote leukemogenesis through blockage of myeloid differentiation [4,5,6]. The expression levels of both genes have been identified as feasible markers for residual disease in AML patients in complete remission (CR) independent of the applied consolidation therapy [15,16,17,18,19]
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