Leukemia secondary to myeloproliferative neoplasms

Abstract

Secondary acute myeloid leukemias (AMLs) evolving from an antecedent myeloproliferative neoplasm (MPN) are characterized by a unique set of cytogenetic and molecular features distinct from de novo AML. Given the high frequency of poor-risk cytogenetic and molecular features, malignant clones are frequently insensitive to traditional AML chemotherapeutic agents. Allogeneic stem cell transplant, the only treatment modality shown to have any beneficial long-term outcome, is often not possible given the advanced age of patients at time of diagnosis and frequent presence of competing comorbidities. Even in this setting, relapse rates remain high. As a result, outcomes are generally poor and there remains a significant unmet need for novel therapeutic strategies. Although advances in cancer genomics have dramatically enhanced our understanding of the molecular events governing clonal evolution in MPNs, the cell-intrinsic and -extrinsic mechanisms driving leukemic transformation at this level remain poorly understood. Here, we review known risk factors for the development of leukemic transformation in MPNs, recent progress made in our understanding of the molecular features associated with leukemic transformation, current treatment strategies, and emerging therapeutic options for this high-risk myeloid malignancy.

Graphical abstract

Figure 1.

Frequency of individual somatic mutations in de novo AML vs post-MPN AML. Mutation data from a large de novo AML cohort in comparison to those frequently found in post-MPN AML reveal differences in the frequencies of commonly-mutated genes implicated in these two conditions.

Figure 2.

Various routes to leukemic transformation in MPNs. Mutations in epigenetic modifiers (ie, TET2, ASXL1, etc) can be acquired before or after JAK2V617F. Over time, additional somatic genetic and/or epigenetic remodeling events, under influence of various cellular-intrinsic or -extrinsic factors, promote progressive proliferative and self-renewal capacity upon the expanding cell population, ultimately leading to blast-phase transformation. Notably, in many instances, leukemic clones arise from a JAK2V617F wild-type (yellow) cell population suggesting evolution of a separate, coexisting clonal process. In the case of TP53-mutant post-MPN AML (red box), literature suggests a distinct route to leukemic transformation in which “second-hit” loss of heterozygosity (LOH) of TP53 in a preexisting JAK2V617F/TP53 heterozygous-mutant clone results in rapid clonal expansion, chromosomal instability, and blast-phase transformation.