RUNX1 and CBFβ Mutations and Activities of Their Wild-Type Alleles in AML

Abstract

Mutations in RUNX1 and CBFB have long been recognized as important in hematological malignancies. Point mutations and deletions of RUNX1 are frequently found in myelodysplastic syndrome, myeloproliferative disease, and acute myeloid leukemia. Germline mutations in RUNX1 are associated with familial platelet disorder with predisposition to AML. In addition, as will be discussed in other chapters, both RUNX1 and CBFB are involved in recurrent chromosomal rearrangements in leukemia. More recently, roles for the non-mutated RUNX1 and CBFB genes have been identified in multiple leukemia subtypes. This chapter will discuss the roles of RUNX1 and CBFB, both in diseases caused by their mutations or deletions, as well as in the context of chromosomal rearrangements.

HDAC1 Is a Required Cofactor of CBFβ-SMMHC and a Potential Therapeutic Target in Inversion 16 Acute Myeloid Leukemia

“…Entinostat has also been shown to cause differentiation and apoptosis in leukemia cells expressing the fusion gene MLL-AF9. Although this fusion protein is not known to interact with HDAC1, it does require RUNX1 expression for its leukemogenic activity (48)(49)(50). These results may imply a common role for HDAC1 in RUNX1dependent leukemia.…”

RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1

“…14 In AML, RUNX1 mutations often co-occur with mutations in FLT3, MLL-PTD, DNMT3A, ASXL1, CEBPA, NRAS, KIT, and IDH1/2. 21,22,26 Germline, monoallelic, and intragenic mutations and deletions in RUNX1 cause the highly penetrant (;40%) autosomal dominant familial platelet disorder (FPD), with a propensity to evolve into myeloid malignancy (FPD-MM). 20,[26][27][28] Previous reports showed that wild-type RUNX1 (wtRUNX1) activity is necessary to sustain leukemia caused by RUNX1-RUNXT1, CBFb-SMMHC, and MLL-ENL or MLL-AF9.…”

“…21,22,26 Germline, monoallelic, and intragenic mutations and deletions in RUNX1 cause the highly penetrant (;40%) autosomal dominant familial platelet disorder (FPD), with a propensity to evolve into myeloid malignancy (FPD-MM). 20,[26][27][28] Previous reports showed that wild-type RUNX1 (wtRUNX1) activity is necessary to sustain leukemia caused by RUNX1-RUNXT1, CBFb-SMMHC, and MLL-ENL or MLL-AF9. 26,[29][30][31] However, in AML expressing mtRUNX1, the effects of knockdown of RUNX1 have not been determined.…”

“…20,[26][27][28] Previous reports showed that wild-type RUNX1 (wtRUNX1) activity is necessary to sustain leukemia caused by RUNX1-RUNXT1, CBFb-SMMHC, and MLL-ENL or MLL-AF9. 26,[29][30][31] However, in AML expressing mtRUNX1, the effects of knockdown of RUNX1 have not been determined. The present studies show that short hairpin RNA (shRNA)-mediated knockdown of mtRUNX1 and wtRUNX1 inhibited in vitro and in vivo AML growth and survival of immune-depleted mice engrafted with AML cells expressing mtRUNX1.…”

Preleukemia and Leukemia-Initiating Cell Activity in inv(16) Acute Myeloid Leukemia

“…RUNX1 and CBFB genes are recurrently mutated in AML. Although a variety of mutations in RUNX1 have been described in hematologic malignancies, the only rearrangement associated with CBFB is the pericentric inversion inv(16)(p13q22), henceforth inv(16), in leukemia ( 7 – 9 ). The inv(16) generates the fusion gene CBFB-MYH11 , encoding the leukemia fusion protein CBFβ–SMMHC ( 10 ).…”