IntroductionA growing body of evidence supports a role for members of the mammalian Hox homeobox gene family of transcription factors in the regulation of hematopoiesis. 1 In a subgroup of human myeloid leukemias, the HOXA9 gene is involved in a recurrent translocation between chromosomes 7 (NUP98) and 11 (HOXA9), resulting in a fusion transcript that encodes the NUP98-HOXA9 oncoprotein. 2,3 Recently, the expression of HOXA9 was also shown to be the single most highly correlating factor (of 6817 genes tested) for poor prognosis in human acute myeloid leukemia (AML), 4 possibly indicating a broader role for this gene in human leukemia beyond that caused by its chromosomal translocations.The leukemogenic potential of Hoxa9 was directly demonstrated by the development of AML in mouse bone marrow transplantation chimeras that received a graft of primitive hematopoietic cells engineered by retroviral gene transfer to overexpress Hoxa9. 5,6 Although the latency for the development of AML in these chimeras is much shorter than reported for other similar Hox gene chimeras (ie, Hoxa10, Hoxb3, Hoxb8), overexpression of Hoxa9 alone is not sufficient to induce leukemia, and additional somatic mutation(s) are needed. [6][7][8][9] In leukemic transformation, genetic interactions have been demonstrated between Hoxa9 and molecules such as Meis1 and E2A-PBX1, 5,6 both of which can bind DNA cooperatively with Hoxa9. 10,11 This suggests the presence of a leukemogenic complex, which includes Hoxa9 and potentially some of its DNA-binding cofactors.In normal human CD34 ϩ bone marrow cells, HOXA9 is preferentially expressed in subfractions that are highly enriched for primitive long-term culture-initiating cells or myeloid progenitor cells, and its expression is significantly reduced in the erythroid lineage. 12,13 This pattern of Hoxa9 expression is conserved in murine hematopoietic cells, with high levels detected in the Sca-1 ϩ lineage-negative (LinϪ) bone marrow subpopulation that is enriched for primitive hematopoietic cells, whereas much lower levels are present in the progenitor-depleted fraction (eg, Sca-1 Ϫ Lin ϩ ). 14,15 Hoxa9 is also expressed in purified subpopulations of B and T lymphoid cells, although at levels much lower than those found in primitive bone marrow cells. 14 Analysis of the Hoxa9 null mutant mice showed that lack of Hoxa9 caused a significant decrease in bone marrow myeloid and pre-B-cell progenitors, and Hoxa9 Ϫ/Ϫ myeloid progenitors have a blunted response to granulocyte colony-stimulating factor, a growth factor known to enhance the production and release of granulocytes from the bone marrow. 14 Although adult thymocyte development was only mildly abnormal in Hoxa9 Ϫ/Ϫ mice, the fetal thymus cellularity was reduced 5-to 10-fold, due in part to a delay in thymocyte progression from immature single-positive (T-cell receptor-negative) to double-positive (ie, CD4 ϩ CD8 ϩ ) T cells. 14,16 In contrast to lymphoid and myeloid progenitor cells in the Hoxa9 Ϫ/Ϫ mice, no significant decrease was detected in more...

SUMMARY Studying 830 pre-B ALL cases from four clinical trials, we found that human ALL can be divided into two fundamentally distinct subtypes based on pre-BCR function. While absent in the majority of ALL cases, tonic pre-BCR signaling was found in 112 cases (13.5%). In these cases, tonic pre-BCR signaling induced activation of BCL6, which in turn increased pre-BCR signaling output at the transcriptional level. Interestingly, inhibition of pre-BCR-related tyrosine kinases reduced constitutive BCL6 expression and selectively killed patient-derived pre-BCR+ ALL cells. These findings identify a genetically and phenotypically distinct subset of human ALL that critically depends on tonic pre-BCR signaling. In vivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR+ ALL.

In the last decade it has become clear that homeobox containing genes (HOX genes) not only play a significant role in regulating body formation, but in addition, they are contributing to organization and regulation of hematopoiesis. Modern molecular technologies showed that deregulated expression or disruption of Hox genes can lead to altered characteristics of blood cells or disturbance of blood cell development. In this paper we review the role of HOX proteins in hematopoiesis and leukemogenesis and speculate about their possible target genes and involvement in lymphomagenesis.