Leukemogenic transformation by HOXA cluster genes

Abstract

IntroductionNext to their role in determining the identity of body segments throughout embryogenesis, the clustered HOX homeobox genes also control differentiation and self-renewal of hematopoietic stem and precursor cells. In particular genes of the HOXA cluster and to a lesser extent of the HOXB group are highly transcribed in hematopoietic precursors. During maturation HOX expression is gradually extinguished. 1 An ectopic expression of HOX genes therefore has profound consequences for hematopoiesis. One prominent example is HOXB4, which controls stem cell pool size. As a consequence, artificial introduction of HOXB4 can be used to expand hematopoietic stem cell numbers. 2,3 A relative overexpression of HOX genes also is a hallmark of many hematological malignancies, and a high concentration of HOXA9 in leukemic blasts has been shown to be an adverse prognostic parameter. 4 Proper HOX control is frequently lost in acute myeloid leukemia (AML), where these genes can be erroneously activated by mutations of their upstream regulators CDX2 and CDX4. [5][6][7][8] Also, mixed-lineage leukemia (MLL) fusion proteins in MLL induce aberrant HOX transcription, and the HOX expression pattern is a characteristic diagnostic criterion for this type of leukemia. 9 In several cases of T-cell acute lymphoblastic leukemia (ALL), a recurrent inversion inv(7)(p15q34) places part of the HOXA cluster under control of the promoter normally driving the T-cell receptor. As a consequence, this genetic aberration leads to inappropriate HOX transcription. 10,11 In addition, various HOX genes are directly involved in leukemogenic fusions with nucleoporins. HOXA9, for example, is fused to NUP98 by a translocation t(7;11)(p15;p15) that is frequently detected as sole genetic anomaly in AML. 12,13 In addition to these clinical observations, direct experimental evidence also illustrates the oncogenic capacity of HOX proteins.HOXA9 and HOXA7, as well as their protein dimerization partner MEIS1 (another homeobox gene of the "3-amino-acid-loopextension ϭ TALE" class), frequently were coactivated in retroviral tagging experiments. 14 Likewise, artificial overexpression of HOXA7, HOXA9, or HOXA10 in combination with MEIS1 caused leukemia in animal models. 1 The coexpression of MEIS1 accelerates HOX-driven leukemogenesis by activation of genes that also are present in hematopoietic stem cells. [15][16][17][18] In summary, all available data point to a major role in particular of the "posterior" HOXA genes A7 to A10 as important hematopoietic oncogenes. Despite this HOX dominance in leukemia, a systematic, comparative assessment of the transforming capacity of all HOXA genes has never been undertaken. It is unknown why posterior HOX genes appear to predominate. Moreover, there are conflicting results of whether individual HOX genes are necessary for transformation or whether leukemogenesis is the consequence of a coordinated action involving the combined action of several HOX genes. Especially in the case of MLL fusion proteins that activate expre...

A human ESC model for MLL-AF4 leukemic fusion gene reveals an impaired early hematopoietic-endothelial specification

“…MLL fusions are well-known positive regulators of homeobox gene expression [18,19]. Interestingly, Stam et al [19] have reported the existence of two distinct subgroups among t(4;11)-positive infant ALL cases characterized by the absence or presence of HOXA expression, with those patients lacking HOXA expression being at extreme high risk of disease relapse.…”

“…As MLL fusions are positive regulators of homeobox gene expression [18][19][20], we next performed microarray gene expression in NEO and MLL-AF4 hESCs to specifically analyze the impact of MLL-AF4 expression on the Hox gene family transcriptome in hESCs. As detailed in Figure 1E, 88.9% of the Hox family genes differentially expressed between MLL-AF4 and NEO hESCs resulted to be upregulated in MLL-AF4 hESCs, including the consistently upregulated targets of MLL fusions HOXA9 and MEIS1.…”

An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

“…The considered cut-off level for dichotomizing white blood cell count was 100x10 9 /L. The considered cut-off ratio for dichotomizing HOXA status was defined as the lowest HOXA ratio associated with a genetic abnormality known to activate HOXA.…”

“…[4][5][6] The last subgroup is characterized by aberrant activation of the HOXA gene locus on chromosome 7. Homeobox (HOX) factors normally regulate the transcription of genes that are critical for development and proliferation .7,8 In murine models, Hoxa overexpression induces a hematopoietic differentiation block and leukemic transformation of normal progenitor cells, [9][10][11] suggesting that HOXA overexpression may directly affect the biology of human T-ALL.…”

Connectivity mapping identifies HDAC inhibitors for the treatment of t(4;11)-positive infant acute lymphoblastic leukemia

“…As these genes remained hypermethylated and silenced in normal hematopoietic cells, the loss of suppressive promoter methylation and consequent activation of transcription of these genes in t(4;11)-positive ALL may well have been involved in the transformation process. Supporting this assumption, these genes frequently involve potential proto-oncogenes, like MYC, 33 HOXA9, 34 SET, 35 RUNX1, 36 RAN, 37 PARK7, 38,39 and DIAPH1. 40 Moreover, several of the hypomethylated genes that we identified in this study, that is, ZCCHC7, HOXA9 and MYC, have all been shown to be activated by the MLL-AF4 fusion itself via H3K79 methylation through the recruitment of DOT1L.…”