Are kinases factors in core binding factor leukemia?
Are kinases factors in core binding factor leukemia?
复制标题
激酶因子是核心结合因子白血病吗？
DOI：
10.1080/10428190903174375
复制
发表时间：
2009
影响因子：
2.6
通讯作者：
Corey,SethJ
中科院分区：
文献类型：
--
作者：
Andolina,JeffreyR;Corey,SethJ
A high degree of molecular heterogeneity exists among the acute myeloid leukemias (AMLs). Approximately 10–20% of AML cases involve the rearrangement of either the a or b subunit of the core binding factor (CBF)[1]. In adults, both CBFa and CBFb rearrangements result in AML more sensitive to cytarabine [2]. Hence, CBF leukemias carry a more favorable prognosis [3]. However, not all with CBF leukemia go into complete remission or have a sustained remission, and only half of these patients are cured [4]. What other factors might further stratify the patients? CBFs are heterodimeric transcription factors, consisting of RUNX1 and CBFb [5]. As a complex, they play critical roles during hematopoiesis. In the translocation (8; 21)(q22; q22), the chromosomal rearrangement results in the fusion of RUNX1 (AML1/CBFa) gene with that of ETO (eight twenty-one). The DNA binding domain of RUNX1, but not the activation domain, is retained in the fusion. The RUNX1-ETO gene product interferes with the unaffected RUNX1, an intact transcriptional factor. ETO binds the co-repressors N-CoR and mSin3 and recruits histone deacetylase (HDAC) activity [6]. In the inversion 16 or translocation (16; 16)(p13; q22), CBFb forms a chimeric gene with the myosin heavy chain (MYH11, also referred to as SMMHC)[7]. The resulting transcript encodes a protein consisting of the N-terminus of the CBFb in frame with the C-terminal portion of the smooth muscle myosin heavy chain. Bone marrow eosinophilia often accompanies the acute monoblastic leukemia.Infection of mouse bone marrow cells with AML1-ETO or CMFb-MYH11 does not result in AML, strongly suggesting that other signaling molecules must be disturbed to produce human disease [8]. The chromosomal translocations are insufficient to cause leukemia; rather, they initiate the disease in the setting of additional genetic mutations. Four processes transform a normal hematopoietic progenitor cell into a leukemic one: self-renewal, loss of apoptosis, altered response to growth signals, and block in differentiation. Gain-of-function mutations of receptor protein tyrosine kinases c-Kit and Flt3 and non-receptor protein tyrosine kinase Jak2 may be viewed as promoting leukemia by affecting apoptosis or factor independence [9]. Flt3 is one of the most commonly affected genes, either manifesting as a gain of function mutation in the kinase domain or codon duplication in the juxtamembrane region [10]. The gain of function mutation in Jak2 is found in patients with myeloproliferative disease, especially in polycythemia vera [11, 12]. When transfected into murine bone marrow mononuclear cells, gain-offunction mutations of c-Kit, Flt3, or Jak2 result in myeloproliferative disease. Although the primary endpoint of the study was to determine the association of c-Kit mutations with clinical outcome of CBF leukemias, Markova and investigators also determined the incidence and prognostic impact of Flt3 and Jak2V617F mutations [13]. The investigators made several observations:(1) quantitative PCR of bone marrow was more sensitive than peripheral blood, and, as expected, MRD
