The Study of SALL4 Gene and BMI-1 Gene Expression in Acute Myeloid Leukemia Patients

Rania Shafik Swelem, MD; Dalia AbdelMoety Elneely, MD; Ahmed Abdel Rahman Shehata, MD

Disclosures

Lab Med. 2020;51(3):265-270. 

In This Article

Abstract and Introduction

Abstract

Background: In acute myeloid leukemia (AML), many genes have been studied as prognostic markers. SALL4 is expressed constitutively in human leukemia cell lines and primary AML cells. BMI-1 is expressed highly in purified hematopoietic stem cells (HSCs), and its expression declines with differentiation.

Objective: To study the expression levels of SALL4 and BMI-1 and their clinical significance in patients with AML.

Methods: The study was performed with 60 patients newly diagnosed with AML and 50 control individuals. SALL4 and BMI-1 expression detection were performed using real-time polymerase chain reaction (PCR).

Results: The expression of SALL4 and BMI-1 was significantly higher in cases of AML and showed a strong association with failure to achieve complete remission (CR) or with relapse (P = .02, P = .03, respectively). In multivariate analysis, these genes were the most powerful independent predictors of poor prognosis (P = .01 for SALL4, P = .02 for BMI-1).

Conclusion: SALL4 and BMI-1 are significant prognostic factors in AML and could be strong targets for novel types of therapy.

Introduction

Acute myeloid leukemia (AML) is a heterogeneous disease that remains challenging to treat because of patient factors (age and coexisting diseases) and intrinsic biologic factors.[1] Cytogenetics[2] and mutational[3] data are used to divide patients into subgroups defined according to prognostic factors.[4–7]

Mutated genes were classified into 1 of 9 functional categories: transcription factor fusions, the NPM1 gene, tumor suppressor genes, DNA methylation-related genes, signaling genes, chromatin-modifying genes, myeloid transcription-factor genes, cohesin complex genes, and spliceosome complex genes.[8]

AML development is considered to be a multistep process that requires the collaboration of at least 2 classes of mutations to reach full-blown leukemia. Almost a decade ago, Gilliland and Griffin[9] presented a paradigm model for this process, designated the 2-hit model. It comprises class I mutations that activate signal transduction pathways and confers a proliferation advantage on hematopoietic cells, and class II mutations targeting transcription factors and primarily serving to impair hematopoietic differentiation.[10–11]

As an example of class II mutations, BMI-1 and SALL4 are oncogenes that modulate stem-cell pluripotency and play a role in leukemogenesis. The SALL4 zinc-finger transcription factor a member of the SALL gene family, was originally cloned based on sequence homolog to Drosophila spalt(sal). Alternative splicing resulted in 2 variant forms of human SALL4 messenger RNA (mRNA), SALL4A and SALL4B, each having a different tissue distribution.

Recently, SALL4 has been shown to play an important role in maintaining embryonic stem cell (ESC) pluripotency and self-renewal properties. It was demonstrated[12] that SALL4 is expressed constitutively in human leukemia cell lines and primary AML cells. The identification of downstream targets of SALL4 or factors that regulate BMI-1 in leukemogenesis is of significant interest. It was suggested that the SALL4 expression level can potentially be used to guide decision making in the treatment of myelodysplastic syndrome (MDS) and other hematological malignant neoplasms.[12]

The BMI-1 polycomb gene plays an essential role in regulating adult, self-renewing hematopoietic stem cells (HSCs) and leukemia stem cells and is highly expressed in purified HSCs; its expression declines with differentiation. The expression of BMI-1 appears to be important in the accumulation of leukemic cells. We were interested to learn that inhibiting self-renewal in tumor stem cells after deleting BMI-1 can prevent leukemic recurrence. BMI-1 expression is an important marker for predicting the development of MDS and disease progression to AML. Targeting BMI-1 activity might offer more curative success for the hematologic malignant neoplasms associated with its aberrant activity.[13,14] The aims of this study were to investigate the expression levels of SALL4 and BMI-1 genes and their clinical significance in patients with AML.

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