AmplifiedEPOR/JAK2Genes Define a Unique Subtype of Acute Erythroid Leukemia

Abstract

Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome/exome and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains/amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains/amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL.

Erythroid/megakaryocytic differentiation confers BCL-XL dependency and venetoclax resistance in acute myeloid leukemia

“…Intriguingly, a FAB M1 sample expressing high levels of erythroid lineagespecific TFs and harboring an EPOR frameshift mutation leading to the elimination of negative regulatory domains (supplemental Figure 6C) was also highly sensitive to BCL-XL inhibition. Similar EPOR truncating mutations are recurrent driver mutations in erythroleukemia, 5 Ph-like ALL, 50 and erythrocytosis. 51 Although A-1331852 was the most selectively effective against AML with erythroid or megakaryocytic differentiation, these samples also showed sensitivity to the BCL-2/ BCL-XL inhibitor navitoclax (Figure 4A).…”

“…The M6/M7 AML cell lines frequently harbored TP53 mutations (Figure 3A), consistent with patient data. 5,6 Because TP53 loss has been linked to venetoclax resistance and compensatory BCL-XL upregulation, 45 we tested whether TP53 loss drives sensitivity to BCL-XL inhibition. Erythroid/megakaryoblastic cell lines were more sensitive to BCL-XL inhibition even when compared only to TP53-mutated cell lines (supplemental Figure 3).…”

“…3,4 Genetically, patients with AEL are characterized by frequent TP53 (40.3%), STAG2 (20.1%), KMT2A (20.2%), TET2 (16.9%), and NPM1 (14.5%) mutations and poor risk cytogenetics. 5,6 In particular, patients with TP53 mutations have a dismal outcome, and there are few viable treatment options. 5,6 Intriguingly, erythropoietin receptor (EPOR)/JAK2 gains and amplifications were recently identified in TP53mutated cases associated with JAK inhibitor sensitivity in preclinical models.…”

“…5,6 In particular, patients with TP53 mutations have a dismal outcome, and there are few viable treatment options. 5,6 Intriguingly, erythropoietin receptor (EPOR)/JAK2 gains and amplifications were recently identified in TP53mutated cases associated with JAK inhibitor sensitivity in preclinical models. 5 Moreover, targetable signaling mutations are found in 45% of AEL cases, indicating a need for new therapeutic approaches for most of these patients.…”

“…5,6 Intriguingly, erythropoietin receptor (EPOR)/JAK2 gains and amplifications were recently identified in TP53mutated cases associated with JAK inhibitor sensitivity in preclinical models. 5 Moreover, targetable signaling mutations are found in 45% of AEL cases, indicating a need for new therapeutic approaches for most of these patients. 6 AMKL is characterized by excessive production of megakaryoblasts within the bone marrow (BM), extensive myelofibrosis, anemia, and thrombocytopenia.…”