Classical HLA class I (class Ia) downregulation may be the cause of immune escape mechanism by the cancer cells and is well documented in different cancers. Recently it is shown that in leukemia there is a locus specific HLA class Ia downregulation both at the antigenic and transcriptional level. As, so far, no mutation is recorded in HLA genes; so the reason may lies at the expression of different transcription factors (TRFs) that regulate its expression. Reports suggest that there is an alteration of the constitutive region binding TRFs of the HLA promoter in leukemia. Though there is upregulation of some inducible region binding TRFs, but they are unable to transcribe the HLA class Ia genes. This indicates the accessory role of the inducible binding TRFs. Absence of non-classical HLA class I (class Ib) in leukemic cells may give us the molecular rationale for the success of NK cell mediated immunotherapy. Interestingly, neutrophils (PMNs) of normal volunteers in contact with leukemic cells showed HLA class II expression and oxidative damage towards the leukemic cells. So, PMNs can be utilized for the management of infections under the condition and for leukemia immunotherapy.