Phenotypically-defined stages of leukemia arrest predict main driver mutations subgroups, and outcome in acute myeloid leukemia

Abstract

Classifications of acute myeloid leukemia (AML) patients rely on morphologic, cytogenetic, and molecular features. Here we have established a novel flow cytometry-based immunophenotypic stratification showing that AML blasts are blocked at specific stages of differentiation where features of normal myelopoiesis are preserved. Six stages of leukemia differentiation-arrest categories based on CD34, CD117, CD13, CD33, MPO, and HLA-DR expression were identified in two independent cohorts of 2087 and 1209 AML patients. Hematopoietic stem cell/multipotent progenitor-like AMLs display low proliferation rate, inv(3) or RUNX1 mutations, and high leukemic stem cell frequency as well as poor outcome, whereas granulocyte–monocyte progenitor-like AMLs have CEBPA mutations, RUNX1-RUNX1T1 or CBFB-MYH11 translocations, lower leukemic stem cell frequency, higher chemosensitivity, and better outcome. NPM1 mutations correlate with most mature stages of leukemia arrest together with TET2 or IDH mutations in granulocyte progenitors-like AML or with DNMT3A mutations in monocyte progenitors-like AML. Overall, we demonstrate that AML is arrested at specific stages of myeloid differentiation (SLA classification) that significantly correlate with AML genetic lesions, clinical presentation, stem cell properties, chemosensitivity, response to therapy, and outcome.

Imatinib with intensive chemotherapy in AML with t(9;22)(q34.1;q11.2)/BCR::ABL1. A DATAML registry study.

“…Immunophenotyping AML are phenotypically strati ed based on stage of leukemia arrest, which characterizes the differentiation block in the human hematopoietic hierarchy. 12 We investigated the phenotype of 11 de novo BCR::ABL1 + AML and 8 CML-BP. Both groups exhibited a signi cant enrichment in multipotent progenitor-like phenotype (MPP-L, odds ratio 4.83, p=0.008 and 5.42, p=0.0005, respectively) compared with a series of 2230 patients with BCR::ABL1 negative AML (Figure 2A and Supplemental Figure 1).…”

Leukemic progenitor compartment serves as a prognostic measure of cancer stemness in patients with acute myeloid leukemia

“…Although the field has invested considerable effort to develop different functional and molecular measures to estimate features of leukemic stemness in samples obtained from patients with AML, few studies have comprehensively compared different measurements across the same set of patients. 19 Using a heterogeneous group of 22 patients with AML (patients #2–23; Table S1 ), we first prioritized functional biological testing to identify LSCs and LPCs. Our functional analyses consisted of a series of in vivo and in vitro assays using xenograft modeling to rigorously detect LSCs, as well as semi-solid CFU assays to detect LPCs ( Figure 1 A).…”

The Growing Role of the Bh3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia

“…In fact, AMLs harboring RUNX1 mutations or inv(3) are among the different AMLs blocked at the earliest stage of hematopoietic stem cell/progenitor-like differentiation. 105 Secondary AMLs. Secondary AMLs (sAMLs) derive from the leukemic transformation of preceding myeloid neoplasia, either a myelodysplastic syndrome (MDS) or of myeloproliferative neoplasms (primary myelofibrosis, polycythemia vera, or essential thrombocytosis).…”

“…In fact, AMLs harboring RUNX1 mutations or inv(3) are among the different AMLs blocked at the earliest stage of hematopoietic stem cell/progenitor-like differentiation. 105 …”